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Published in final edited form as: Pharmacol Ther. 2023 Jun 29;248:108487. doi: 10.1016/j.pharmthera.2023.108487

Protoporphyrin IX-Induced Phototoxicity: Mechanisms and Therapeutics

Zahir Hussain a,‡, Qian Qi a,‡, Junjie Zhu a, Karl E Anderson b, Xiaochao Ma a,*
PMCID: PMC10529234  NIHMSID: NIHMS1915006  PMID: 37392940

Abstract

Protoporphyrin IX (PPIX) is an intermediate in the heme biosynthesis pathway. Abnormal accumulation of PPIX due to certain pathological conditions such as erythropoietic protoporphyria and X-linked protoporphyria causes painful phototoxic reactions of the skin, which can significantly impact daily life. Endothelial cells in the skin have been proposed as the primary target for PPIX-induced phototoxicity through light-triggered generation of reactive oxygen species. Current approaches for the management of PPIX-induced phototoxicity include opaque clothing, sunscreens, phototherapy, blood therapy, antioxidants, bone marrow transplantation, and drugs that increase skin pigmentation. In this review, we discuss the present understanding of PPIX-induced phototoxicity including PPIX production and disposition, conditions that lead to PPIX accumulation, symptoms and individual differences, mechanisms, and therapeutics.

Keywords: Heme, Protoporphyrin IX, Erythropoietic protoporphyria, X-linked protoporphyria, Phototoxicity

1. Introduction

Under physiologic conditions, the production and disposition of protoporphyrin IX (PPIX), the immediate precursor of heme, are tightly regulated and maintained at low levels in the body (Brun and Sandberg, 1991). Whenever the intricate regulation of heme biosynthesis is perturbed due to certain disorders of enzymes or transporters, PPIX may accumulate in the liver and erythrocytes, potentially reaching a toxic level (Brun and Sandberg, 1991). It is well-recognized that over-accumulated PPIX leads to dermal phototoxicity due to its electron-rich structure (Lim, 1989). The severity of protoporphyria symptoms varies even among patients with the same mutation and degree of inherited enzyme deficiency, suggesting that additional factors contribute to PPIX accumulation and the severity of PPIX-induced phototoxicity (Fukuda et al., 2016; Ged et al., 2004; To-Figueras et al., 2007). Despite earlier reports of the clinically important pathophysiology of PPIX accumulation (Brun and Sandberg, 1991; Kosenow and Treibs, 1953; Magnus et al., 1961), the molecular mechanisms of PPIX-induced phototoxicity are not wellunderstood.

In the clinic, abnormal accumulation of PPIX occurs in patients with erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) (Balwani, 2019; Piomelli et al., 1975). EPP is the most common type of protoporphyria, affecting 1 in 50,000 to 200,000 individuals (Elder et al., 2013; Ramanujam and Anderson, 2015). XLP accounts for up to 10% of the patients diagnosed with protoporphyria in North America and 2% in Europe (Balwani, 2019). With light exposure, early or prodromal symptoms of protoporphyrias include itching and burning, followed by increasingly severe pain, erythema, and edema after more prolonged exposure, but usually without formation of blisters (Balwani, 2019). The time to first symptoms varies considerably among patients. Currently, options for the management of protoporphyrias include opaque clothing, sunscreens, phototherapy, blood therapy, antioxidants, bone marrow transplantation, and drugs that increase skin pigmentation (Dickey et al., 2022; Diffey and Farr, 1991; Heerfordt et al., 2023; Minder et al., 2009; Tintle et al., 2014). This review discusses our present knowledge regarding PPIX-induced phototoxicity from preclinical and clinical perspectives. PubMed® (https://pubmed.ncbi.nlm.nih.gov/) was used as the major database for the current review and supplemented with other databases such as Elsevier.

2. PPIX production and disposition

PPIX is mainly produced in the bone marrow (~85%) and secondarily in the liver (15%) through the heme biosynthesis pathway with the involvement of 8 enzymes (Fig. 1). It starts with the condensation of glycine and succinyl-CoA catalyzed by 5-aminolevulinic acid synthase (ALAS), the rate-limiting enzyme of the heme biosynthesis pathway, to form 5-aminolevulinic acid (ALA) in the mitochondria (Burch et al., 2018; Gibson et al., 1958; Phillips, 2019; Strand et al., 1970; Tschudy et al., 1975). Two isoforms of ALAS have been identified: ALAS1 is expressed in all tissues including the liver, and ALAS2 is expressed only in the bone marrow (Cable et al., 2000; Kolluri et al., 2005; Melefors et al., 1993). Next, ALA is transported out from mitochondria to cytoplasm and goes through four enzyme-dependent steps to form coproporphyrinogen III (Gibson et al., 1955). Coproporphyrinogen III is transported back into mitochondria and oxidized by coproporphyrinogen oxidase to produce protoporphyrinogen IX, which is further oxidized to produce PPIX by protoporphyrinogen oxidase (Bogorad, 1958a; b). The final step is the incorporation of iron into PPIX to produce heme, catalyzed by the enzyme ferrochelatase (FECH) (Riethmueller and Tuppy, 1964).

Fig. 1.

Fig. 1.

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Major enzymes and transporters that are associated with protoporphyrin IX (PPIX) production and disposition. PPIX is an intermediate in the heme biosynthesis pathway, in which aminolevulinic acid synthase (ALAS) is the rate-limiting enzyme and ferrochelatase (FECH) is the enzyme that converts PPIX to heme. The ATP-binding cassette subfamily G member 2 (ABCG2) transports PPIX out of mitochondrion and the cell for excretion. Glycine transporter 1 (GlyT1), ABCB6, and the mitoferrin 1(MFRN1)-ABCB10 complex are also involved in the heme biosynthesis pathway, which transport glycine, coproporphyrinogen III (CPgen III), and iron, respectively. SCoA, Succinyl-coenzyme A. Created by Biorender.

In addition to enzymes, several transporters are involved in PPIX production and disposition (Fig. 1). The glycine transporter 1 (GlyT1) is located on the mitochondrial membrane, which feeds glycine into mitochondria to start heme biosynthesis (King and Gunn, 1989; Winter et al., 2016). ATP-binding cassette transporter subfamily B member 6 (ABCB6) is located on the outer mitochondrial membrane, which transports coproporphyrinogen III from cytoplasm back into mitochondria for the last three steps of heme biosynthesis (Krishnamurthy et al., 2006; Ulrich et al., 2012). Mitoferrin-1 (MFRN1) is a mitochondrial transporter responsible for transporting ferrous iron into mitochondria for the last step of heme biosynthesis (Chen et al., 2009). The catalytic activity of MFRN1 requires physical interaction with another mitochondrial transporter ABCB10 to form a MFRN1-ABCB10 complex (Chen et al., 2009). ATP-binding cassette transporter subfamily G member 2 (ABCG2) is expressed in both mitochondrial cristae and cell membrane (Austin Doyle et al., 1998; Gottesman et al., 2002; Solazzo et al., 2009). ABCG2 pumps PPIX out of bone marrow cells and red blood cells into plasma (Jonker et al., 2002b), and then PPIX is taken up by hepatocytes and excreted into the bile ducts. ABCG2 also contributes to the excretion of PPIX from hepatocytes to the biliary system and feces, the major pathway for the elimination of PPIX from the body (Ibrahim and Watson, 1968; Thapar and Bonkovsky, 2008; Wang et al., 2019).

3. Conditions that lead to accumulation of PPIX

3.1. FECH mutations and EPP

FECH is responsible for the insertion of iron into PPIX to form heme so that when FECH activity drops to less than 30 percent of the normal level, accumulation of PPIX significantly increases (Balwani, 2019). EPP is caused by loss-of-function mutations of FECH (Labbé et al., 1999). Up to 2003, more than 190 different mutations have been identified for the FECH gene (Stenson et al., 2003). In recent years, several novel FECH mutations have been discovered (Munemoto et al., 2022; Saito et al., 2020; Weiss et al., 2019). Among all the possible mutation types that have been observed in human FECH, including exon skipping, missense, nonsense, and deletion, exon 10 skipping caused by a transversion of A to T in intron 10 is a relatively common type of FECH mutation in EPP patients (Chen et al., 2002; Wang et al., 1993).

3.2. ALAS2 mutations and XLP

XLP is caused by a gain-of-function mutation of ALAS2, which greatly increases the rate of ALA formation in the bone marrow (Whatley et al., 2008a). The mutation increases the enzymatic activity of ALAS2 approximately 1.6- to 3.1-fold compared to the normal ALAS2 activity (Bishop et al., 2013). Specifically, this gain-of-function mutation is caused by deletion-induced frameshift mutation in exon 11 of ALAS2, leading to the change of 19–20 C-terminal amino acids and overall alternation of the secondary structure of ALAS2 (Whatley et al., 2008b). Exon 11 is a key regulator region for ALAS2 so that once mutated, this regulation is no longer functional and ALA becomes overproduced (Fratz et al., 2015). After ALAS2, FECH is the next limiting enzyme in the pathway, so even a mild increase in ALAS2 activity is enough to cause significant PPIX accumulation (Shah et al., 2012).

3.3. Chemicals that causes PPIX accumulation through ALAS induction

Genetic and chemical factors that cause PPIX overproduction in marrow erythroid precursor cells and hepatocytes are quite distinct. The liver endoplasmic reticulum is rich in cytochrome P450 enzymes (CYPs) that turn over rapidly and account for most of the large amounts of heme synthesized in the liver. Most hepatic CYPs are inducible by exogenous and endogenous chemicals, and these inducers can upregulate hepatic ALAS1 expression, resulting in increased synthesis of intermediates in the heme synthesis pathway, including the upstream intermediates that can cause acute attacks of porphyrias and the downstream intermediate PPIX that may potentate the symptoms of EPP (Fraser et al., 2003; Podvinec et al., 2004). Preclinical studies showed that many porphyrinogenic drugs, such as barbiturates, glutethimide, and 2-propyl-2-isopropylacetamide, significantly induced both hepatic CYPs and ALAS (Hamilton et al., 1988). Co-treatment of rifampicin and isoniazid upregulates ALAS1 in mouse liver, leading to hepatic accumulation of PPIX (Li et al., 2013). In addition, ALA loading, for example, during the photodynamic therapy, can bypass the rate limiting enzyme ALAS1, leading to accumulation of PPIX in many tissues including tumors (Kennedy et al., 1990).

3.4. Chemicals that cause PPIX accumulation through FECH suppression or iron deficiency

FECH inhibitors such as salicylic acid and alkylated-PPIX can cause PPIX accumulation (Cole and Marks, 1984; Gupta et al., 2013). Certain porphyrinogenic molecules such as griseofulvin potently inhibit FECH and result in hepatic PPIX accumulation through formation of N-methyl protoporphyrin IX (Holley et al., 1991; Liu et al., 2015). Another group of porphyrinogenic molecules, 5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine and its 4-alkyl substituted analogs, show various potencies in both inducing formation of N-alkyl PPIX and directly inhibiting FECH activity, leading to hepatic PPIX accumulation (Cole et al., 1981; McCluskey et al., 1992; Ortiz de Montellano et al., 1981). Isoniazid, a common drug used as a part of tuberculosis treatment, is reported to cause PPIX accumulation by downregulating FECH protein in mouse liver (Sachar et al., 2016). The significance of these preclinical findings on chemical-induced PPIX accumulation are not clear for EPP/XLP patients. However, these chemicals may potentiate the symptoms of EPP/XLP because of their effects on PPIX accumulation.

Metal ions such as lead, gallium, copper, cadmium, mercury, and aluminum ions can also inhibit FECH with variable potencies (Schauder et al., 2010). In addition, iron chelators such as deferoxamine, ethylenediaminetetraacetic acid, and thiosemicarbazone derivatives, can cause PPIX accumulation by limiting iron availability for FECH activity (Amo et al., 2009; Berg et al., 1996; Gawecki et al., 2019; Troadec et al., 2011b; Yamamoto et al., 2014). Furthermore, deficiency and/or inhibition of iron transporters MFRN1 and ABCB10 restrain the supply of iron and thus reduce FECH activity, leading to hepatic PPIX accumulation (Troadec et al., 2011a).

3.5. Other conditions that lead to PPIX accumulation

PPIX is mainly excreted from the body by biliary excretion (Ibrahim and Watson, 1968; Thapar and Bonkovsky, 2008). Cholestasis is a type of liver disease that results from intra- or extrahepatic biliary obstruction, which impairs hepatic and biliary excretion of PPIX and can lead to progressive increases in circulating levels of PPIX and accelerated progression of liver damage (Yang et al., 2018). Any conditions causing cholestasis such as taking estrogen-based oral contraceptives may therefore increase the risk of PPIX accumulation (Chen et al., 2013). In addition, genetic deficiency of ABCG2 and ABCB6 would decrease PPIX excretion which in turn causes PPIX accumulation (Fukuda et al., 2016; Jonker et al., 2002a; Sakiyama et al., 2021; Tamura et al., 2006). Furthermore, fasting increases the activity of proliferator-activated receptor-γ coactivator 1α, which upregulates ALAS expression, thereby causing PPIX overproduction and accumulation (Handschin et al., 2005).

4. Symptoms of PPIX-induced phototoxicity and individual differences

4.1. Symptoms of PPIX-induced phototoxicity

In EPP and XLP patients with the elevation of circulating levels of PPIX, which is usually life long, sunlight exposure can cause prodromal itching and burning followed by a severely painful non-blistering type of photosensitivity accompanied by erythema, edema, and systemic symptoms. Time to onset of first symptoms can vary from a few minutes to several hours of outdoor activities (Maitra et al., 2019a; Thapar and Bonkovsky, 2008). Prolonged sun exposure may cause vesicles and scarring, and repeated exposure may cause leathery skin thickening, especially on the knuckles and face (Thapar and Bonkovsky, 2008). A “priming effect” of phototoxicity in EPP is well-known, whereby sun exposure on one day enhances sensitivity to sunlight on the following days (Poh-Fitzpatrick, 1989). In a survey regarding the impact of EPP on quality of life, 85% of patients reported the priming effect (Holme et al., 2006). Compared to non-sunlight-primed skin, sunlight-primed skin has significantly more limited tolerance to further sunlight exposure (Heerfordt et al., 2020). The cause of this priming effect is believed to be a light-mediated release of PPIX from erythrocytes to the skin, leading to the increase of photosensitivity for a prolonged period as the skin concentration of PPIX remains high (Heerfordt and Wulf, 2016).

Aside from the primary effects of PPIX-induced phototoxicity, various secondary effects are not negligible. In a cross-sectional study, 46% of EPP patients were found to be deficient in vitamin D because they avoided sunlight exposure (Spelt et al., 2010). This may contribute to low bone mineral density, osteoporosis, and osteopenia in EPP (Allo et al., 2013; Biewenga et al., 2017). In addition, patients with EPP and XLP usually alter their activities and lifestyles to avoid sunlight, which can limit employment opportunities and/or cause depression (Naik et al., 2019a). Children and young adults find it difficult to adapt to their disease and explain it to others (Naik et al., 2019b). Overall, PPIX-induced phototoxicity in EPP and XLP causes a significant decrease in quality of life. Furthermore, roughly 10 to 20 percent of EPP patients develop hepatic dysfunctions and in about 2 to 5 percents of patients, the continued progression of liver damage can lead to death due to cirrhosis or liver failure (Anstey and Hift, 2007; Hagiwara et al., 2022). Moreover, a significant portion of EPP patients developed mild anemia (Wahlin et al., 2011).

4.2. Individual differences in PPIX-induced phototoxicity

Light tolerability varies among individual patients with EPP or XLP. Most patients develop phototoxic symptoms within 30 minutes of sun exposure while some patients can tolerate exposure for several hours (Di Pierro et al., 2022). The detailed mechanisms of individual differences in the development of PPIX-induced phototoxicity remain unclear, but multiple factors have been identified, including genetic modifiers, liver diseases, and chemical modifiers from diets and drugs.

4.2.1. Genetic factors that modulate PPIX-induced phototoxicity

Dysfunctional variants of ABCB6 were found to be strongly correlated with more severe porphyria phenotypes (Fukuda et al., 2016). As for ABCG2, the efflux transporter of PPIX, over 80 polymorphic variants have been reported and 3 of these (Q126stop, S441N, and F489L) are of clinical importance due to their ability to disrupt ABCG2 function (Tamura et al., 2006). These loss-of-function mutants of ABCG2 showed phototoxicity phenotypes when exposed to pheophorbide, an exogenous porphyrin, and reduced hematoporphyrin transportation (Tamura et al., 2006). In another study conducted with a small group of healthy volunteers, 2 dysfunctional variants of ABCG2 (Q126stop and Q141K) were found to be correlated with higher PPIX accumulation in erythrocytes and photosensitivity (Sakiyama et al., 2021). In contrast, genetic dysfunction of ABCG2 protected against phototoxicity in an EPP mouse model by trapping PPIX inside erythrocytes and reducing its exposure to the skin (Wang et al., 2019).

4.2.2. Chemical factors that potentiate PPIX-induced phototoxicity

CYP and ALAS inducers, FECH inhibitors, and iron chelators from diets and medications may enhance phototoxicity by increasing PPIX accumulation (Blakely et al., 2019; Cole and Marks, 1984; Cole et al., 1981; Gupta et al., 2013; Holley et al., 1991; Li et al., 2013; Liu et al., 2015; McCluskey et al., 1992; Ortiz de Montellano et al., 1981; Richarz et al., 2017). In addition, certain medications, such as amiodarone, chlorpromazine, doxycycline, hydrochlorothiazide, and nalidixic acid, have photosensitizing effects and hence, they may exacerbate phototoxicity in porphyria patients (Blakely et al., 2019; Richarz et al., 2017). Furthermore, impaired antioxidant defense may contribute to variability in the severity of PPIX-induced phototoxicity (Böhm et al., 2001).

4.2.3. Liver diseases that potentiate PPIX-induced phototoxicity

Damage to the liver, especially by cholestasis, can reduce its capacity to eliminate PPIX from the body (Sachar et al., 2016; Wagner et al., 2003). Therefore, severe cholestasis in EPP and XLP patients potentiate PPIX-induced phototoxicity (Lyoumi et al., 2011). In addition, albumin is synthesized in the liver and it is an endogenous carrier of PPIX (Cohen and Margalit, 1990; Seery and Muller Eberhard, 1973; Sułkowski et al., 2016). Liver diseases, such as cirrhosis, can decrease albumin production and increase free PPIX levels in the blood, resulting in more severe phototoxicity (Wen et al., 2022). Furthermore, chronic liver diseases decrease antioxidant defense that can potentiate PPIX-induced phototoxicity due to diminished quenching of ROS generated by photodynamic reactions (Li et al., 2021).

5. Mechanisms of PPIX-induced phototoxicity

Phototoxicity is well documented in EPP and XLP, although its molecular mechanisms are not fully understood (Kosenow and Treibs, 1953; Sachar et al., 2016). Here we outlined the current understanding of PPIX-induced phototoxicity in four steps: distribution of PPIX to the skin, light-mediated PPIX excitation, cellular damages, and aberrant repair processes.

5.1. Distribution of PPIX to the skin

The bone marrow is the major site of PPIX synthesis and erythrocytes are reported as the bulk carrier of excess PPIX in the protoporphyrias (Brun and Sandberg, 1991; Puy et al., 2010). ABCG2 is expressed in bone marrow erythroid cells and circulating erythrocytes, contributing to the efflux of PPIX from these cells into plasma (Jonker et al., 2002b). PPIX is increased 10-fold in erythrocytes of ABCG2-deficient mice, indicating that ABCG2 is critical in PPIX efflux (Jonker et al., 2002a). Genetic dysfunction of ABCG2 in normal human subjects was recently reported to be correlated with higher levels of PPIX in erythrocytes, which further supports an important role for ABCG2 in PPIX efflux from these cells (Sakiyama et al., 2021).

The release of PPIX from erythrocytes increases with light exposure (Brun and Sandberg, 1991; Sandberg et al., 1983). It was proposed that loss of affinity of PPIX to intracellular carrier globin proteins due to light exposure causes the release of PPIX through membrane-bound efflux transporters (Brun and Sandberg, 1991). In fact, in EPP patients, this phenomenon of light-induced PPIX-release is believed to occur whenever erythrocytes pass through sunlight-exposed dermal capillaries, which increases the risk of phototoxicity for local endothelial cells (Brun and Sandberg, 1991). Possibly due to the shorter daylight time during winter, higher levels of PPIX trapped in erythrocytes of EPP patients has been observed in the winter (Brun and Sandberg, 1991).

Albumin is the most abundant plasma protein, which binds to PPIX and is considered as a major endogenous carrier for extracellular PPIX (Cohen and Margalit, 1990; Seery and Muller Eberhard, 1973; Sułkowski et al., 2016). In the presence of light, albumin facilitates the transfer of PPIX from erythrocytes to endothelial cells (Brun and Sandberg, 1991). In addition, PPIX also binds to hemopexin and immunoglobulin G in plasma (Brancaleon and Moseley, 2002; Seery and Muller Eberhard, 1973). Furthermore, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) may bind to PPIX in plasma (Beltramini et al., 1987). Though lipoprotein concentration is less than 5% of albumin, their contributions as PPIX carrier may be important because one LDL molecule can bind to fifty molecules of PPIX and these lipoproteins have the potential to transport PPIX to various tissues that express lipoprotein receptors (Brun and Sandberg, 1991).

Dermal endothelial cells, as the primary target of PPIX-induced phototoxicity (Brun and Sandberg, 1991), might be exposed to PPIX through multiple ways (Fig. 2). Dermal endothelial cells could uptake PPIX from plasma, because these cells are surrounded by plasma that is enriched with PPIX (Brun and Sandberg, 1991). In addition, since erythrocytes (diameter 7 μm) need to be squeezed while passing through dermal capillaries (diameter 4 – 5 μm), PPIX may be directly transferred to endothelial cells due to such close proximity to erythrocytes and its large concentration gradient (~ 1 mM) (Brun and Sandberg, 1991; Brun et al., 1990). Apart from the external sources of PPIX from plasma and erythrocytes, skin cells may produce their own PPIX because subcutaneous injection of ALA into mice showed fluorescence in the skin suggesting in situ synthesis (Sima et al., 1981). In addition, topical application of ALA-based photodynamic therapy causes vascular damage in the skin, indicating the synthesis and accumulation of PPIX in endothelial cells (De Bruijn et al., 2007; de Bruijn et al., 2008). Further studies are needed to determine which pathway, including transporter-dependent and independent pathways, is more important for the distribution of PPIX to dermal endothelial cells.

Fig. 2.

Fig. 2.

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Pathways that PPIX is exposed to the endothelial cells of dermal capillaries in EPP. Three mechanisms have been proposed: (1) PPIX is directly transferred from plasma into endothelial cells down the concentration gradient; (2) PPIX in red blood cell (RBC) is transferred into endothelial cells during the squeezing movement of RBC through the contact of cell membranes; and (3) de novo synthesis of PPIX in endothelial cells. N, nucleus. Created by Biorender.

5.2. Light-mediated PPIX excitation

PPIX needs to be excited by light before inducing phototoxicity in the skin (Maitra et al., 2019a; Peterka et al., 1965). When chronic skin lesions of EPP patients were analyzed by electron microscopy, the main abnormality was found to be associated with small blood vessels in the upper part of the dermis (Ryan and Madill, 1968). Such skin abnormalities were absent in the cloth-covered areas of the skin, suggesting that exposure to sunlight is critical for PPIX-associated skin damage (Ryan and Madill, 1968). The maximal absorption wavelength area of PPIX is 400–600 nm, which can easily penetrate the skin and trigger photodynamic reaction in dermal endothelial cells (Mahmoud et al., 2008; Schnait et al., 1975).

PPIX-mediated endothelial damage was found to be specific to long-wave UV (UV-A) light but not short-wave UV light (UV-B) (Schnait et al., 1975). Long-wave UV light comes naturally from sunlight or glass-filtered artificial lamp and matches within the action spectrum of EPP at around 400 nm (Magnus et al., 1961; Schnait et al., 1975). The short-wave UV light (< 310 nm) which spares the dermal areas from injury actually damages the epidermal areas. Since epidermis was reported to contain very little PPIX, the epidermal lesion observed was suggested to be a typical sunburn instead of PPIX-induced phototoxicity (Gog and Schothorst, 1973; Schnait et al., 1975). The acute flare symptoms observed in EPP patients was reproduced in griseofulvin-induced protoporphyria mouse models, which confirmed that exposure to UV-A irradiation and PPIX are two pre-requisites for endothelial damage in dermal vessels (Konrad et al., 1975).

5.3. Cellular damages in the skin caused by PPIX

The acute skin lesion of EPP patients showed epidermal vacuolization and intercellular edema together with endothelial vacuolization and cytolysis in the superficial blood vessels (Lecha, 2003). Over time, accumulation of hyaline material around dermal blood vessels due to the change of vasopermeability causes capillary basement membranes thickening (Di Pierro et al., 2022; Schnait et al., 1975). The mechanisms of skin damages in EPP is associated with light-triggered production of reactive oxygen species (ROS) from PPIX (Ishizuka et al., 2011). Photodynamic reactions of PPIX lead to the formation of ROS including singlet oxygen, hydroxyl radicals, and super oxide anion radicals (Takeshita et al., 2004). The photodynamic reactions of PPIX were proposed to occur by either type-I or type-II photosensitized reactions (Brun and Sandberg, 1991). ROS is well-known for inducing various types of cell damages by reacting with cellular proteins, lipids, and nucleic acids (Girotti, 2001; Kurz et al., 2021). Overall, dermal endothelial cells come to be the primary target of PPIX-induced phototoxicity because: (1) dermal penetrance of long-wave UV light which aligns with the absorbance maxima of PPIX; (2) endothelial cells possesses the highest partial pressure of oxygen which is essential for the photodynamic process of PPIX, and (3) overt sensitivity of endothelial cells to oxidative stress (Brun and Sandberg, 1991).

Apart from the non-specific damage by light-induced PPIX excitation and ROS formation, organelle-specific protein aggregation was also observed in nucleus, endoplasmic reticulum (ER), and lysosome (Maitra et al., 2019a; Maitra et al., 2021). Such organelle-selective protein aggregation occurs through a “porphyrination-deporphyrination” cycle (Maitra et al., 2021). In porphyrination step, PPIX binds to target proteins and distorts tertiary structures (Belcher et al., 2009; Fernandez et al., 2008). If light exposed, photosensitization of this protein-PPIX complex generates singlet oxygen, which oxidizes methionine to form methionine sulfone or sulfoxide, leading to protein aggregation (Maitra et al., 2019b). As PPIX-induced protein aggregations was also noticed in internal organs, which are not exposed to light, endogenous ROS formed due to various reasons such as inflammation may also contribute to PPIX-induced protein aggregation (Maitra et al., 2021).

PPIX-induced phototoxicity is more severe when coupled with perivascular mast cell degranulation (Konrad et al., 1975). Previously, the H1-receptor antagonist terfenadine was shown to reduce the acute flare reaction in EPP patients when irradiated with blue light (Farr et al., 1990). However, phototoxicity of hematoporphyrin derivative in mast-cell deficient mice was similar to controls, suggesting the role of mast cells may not be critical for PPIX-induced phototoxicity (Lim et al., 1986).

5.4. Aberrant repair processes in PPIX-induced phototoxicity

When EPP patients are exposed to sunlight repeatedly, they usually develop thick skin in their cloth-uncovered areas (Murphy, 2003). Electron microscopy of the thick skin areas of EPP patients revealed that the basement membrane adjacent to dermal endothelial cells was largely replicated, layered, and fragmented (Ryan and Madill, 1968). This phenotype was suggested to be the result of consecutive repairs after endothelial injury (Ryan and Madill, 1968). Great amount of mast cells and extravascular erythrocytes were found in this area, indicating the increase of capillary permeability which causes prolonged edema (Ryan and Madill, 1968). This was further supported by the presence of plasma-derived products in the composition of amorphous hyaline deposits within the dermis as previously shown by histochemistry from chronically sun-exposed skin of EPP patients (Ryan, 1966; Ryan and Madill, 1968; Schnait et al., 1975; Timonen et al., 2000).

ER stress was observed in response to PPIX-induced protein aggregations (Elenbaas et al., 2016; Maitra et al., 2019a). In an acute protoporphyria model of zebrafish larvae, PPIX accumulation caused hepatic protein aggregation with multi-organelle alterations including ER (Elenbaas et al., 2016). As a part of an adaptive response, ER stress is well-known to upregulate ER chaperones proteins to repair defective proteins (Ron and Walter, 2007; Rutkowski and Kaufman, 2004). However, persistent ER stress leads to cell death (Lee et al., 2018). In addition, PPIX accumulation inactivates the chaperones resulting in a novel form of ER damage, which distorts the shape of ER compartment as identified under electron microscope (Elenbaas et al., 2016; Maitra et al., 2019a). Such protein aggregation-induced ER stress and ER damage are also likely to occur in PPIX-associated skin phototoxicities. Indeed, inhibition of ER stress was found to protect against cell death in a blue light-induced skin injury model, suggesting a relation between skin phototoxicity and ER stress-induced cell death (Zhu et al., 2022).

6. Therapeutic approaches for PPIX-induced phototoxicity

Since PPIX, light, and ROS are key players in the phototoxicity experienced by patients with EPP and XLP, current therapeutic approaches aim to shield the skin from light penetration, prevent PPIX excitation, and scavenge free radicals (Minder et al., 2009; Tintle et al., 2014). In recent years, novel strategies were tested in vitro and in animal models with the aim of reducing PPIX accumulation by restoring FECH activity or modulating the transporters related to PPIX biosynthesis or disposition. Here, we summarize these approaches and discuss their mechanism of action, efficacy, and limitations for the management of PPIX-induced phototoxicity.

6.1. Current approaches

6.1.1. β-carotene

β-carotene was reported to offer photoprotection to patients with EPP in 1970 (Mathews-Roth et al., 1970). After oral administration, this carotenoid compound accumulates in the epidermis and reduces light penetration and scavenges free radicals (Mathews-Roth, 1998; Tintle et al., 2014). Typical oral β-carotene dosing is 100–300 mg/day in adults, with a target serum carotene level of 6–8 mg/L (Tintle et al., 2014). Improved light tolerance and reduced light sensitivity was found in 86% patients within 1–3 months of starting treatment (Minder et al., 2009; Tintle et al., 2014). However, another randomized controlled study found no significant efficacy of β-carotene in EPP patients (Corbett et al., 1977). Regarding the side effects of β-carotene, it makes the skin yellowish and may increase the risk of pulmonary malignancy in smokers (Mathews-Roth, 1998; Minder et al., 2009; Tintle et al., 2014).

6.1.2. Phototherapy

Narrowband UV-B phototherapy can improve light tolerances in EPP patients (Roelandts, 1995; Tintle et al., 2014), although it may potentiate erythema, pruritus, skin photoaging, and risk of skin cancer (Collins and Ferguson, 1995). Improved light tolerance by UV-B phototherapy is believed to result from increased skin pigmentation and epidermal thickening (Tintle et al., 2014; Warren and George, 1998). However, the sample size was small in these uncontrolled studies using narrowband UV-B therapy and phototoxic symptoms were only improved in some but not all the patients (Collins and Ferguson, 1995; Sivaramakrishnan et al., 2014). Larger-scale and controlled studies are needed in the future to evaluate the safety and efficacy of UV-B phototherapy in EPP.

6.1.3. Afamelanotide

Afamelanotide is an α-melanocyte-stimulating hormone analog that induces the synthesis of melanin and eumelanin, leading to epidermal hyperpigmentation (Tintle et al., 2014), and is FDA-approved for treatment of EPP (Minder et al., 2009; Wu and Cotliar, 2021). Afamelanotide also has antioxidant and anti-inflammatory activity (Tintle et al., 2014). A three-year observational study showed that afamelanotide increased phototoxic burn tolerance time and quality of life in EPP patients (Barman-Aksozen et al., 2020). The most common adverse effects observed in clinical studies were nausea (19%), headache (20%), and implant site reactions, including discoloration, pain, hematoma or erythema (21%) (Langendonk et al., 2015). A potential drawback is that implantation by a health care professional is required, which may be inconvenient for some patients (Langendonk et al., 2015).

6.1.4. Bone marrow transplantation

Since the bone marrow is the major site of PPIX production, bone marrow transplantation is often discussed as treatment for protoporphyrias (Casanova-Gonzalez et al., 2010). It was reported in 2021 that 9 patients underwent successful bone marrow transplantation and were cured of EPP and no longer had phototoxic symptoms (Wang et al., 2021). One case who was cured of protoporphyria was a child with XLP (Butler et al., 2015). Cost and the risk of bone marrow transplantation are the major drawbacks of this therapeutic strategy (Wang et al., 2021). In addition, it is plausible that some patients could not be cured by bone marrow transplantation, especially for liver toxicity, because PPIX is also produced in the liver.

6.1.5. Other available approaches

Antioxidants, such cysteine, N-acetylcysteine, and vitamin C, have been reported to benefit EPP patients by quenching ROS formed in PPIX-induced phototoxicity (Boffa et al., 1996; Mathews-Roth et al., 1994; Minder et al., 2009). However, their effectiveness is limited because they do not reduce PPIX accumulation in tissues or prevent light-induced PPIX excitation. Nevertheless, antioxidants are sometimes used as adjuvants together with the above-mentioned approaches for EPP therapy. In addition, opaque clothing is commonly used by EPP patients, which can block visible light (Heerfordt et al., 2020). Special sunscreen with high sun protection factor is also frequently used for EPP patients with phototoxic symptoms (Diffey and Farr, 1991; Thapar and Bonkovsky, 2008). It has been shown that microfine titanium dioxide sunscreen significantly increased light tolerance in EPP patients (Diffey and Farr, 1991). In recent couple decades, a number of improved sunscreens have been developed with similar or greater ability to protect EPP patients from sunlight (Moseley et al., 2001; Petersen et al., 2014). Furthermore, blood therapy to exchange red blood cells can effectively lower circulating PPIX concentration, but it may cause infection and iron overload in a long term (Leaf and Dickey, 2023). Additionally, red blood cell exchange and plasmapheresis are ineffective in preventing liver damage or reversing the progression towards liver failure in EPP patients (Eichbaum et al., 2005; Pagano et al., 2012).

6.2. Approaches under development

6.2.1. Dersimelagon

Dersimelagon (MT-7117), is currently undergoing a phase 3 clinical trial for treatment of EPP and XLP (Mitsubishi Tanabe Pharma Development America, 2021). It is a potent melanocortin 1 receptor agonist that induces the synthesis of eumelanin, leading to skin hyperpigmentation (Suzuki et al., 2022). Various studies on dersimelagon showed good tolerance and favorable pharmacokinetic profiles among healthy participants with diverse ethnicities and age groups (Ogasawara et al., 2023; Ogawa et al., 2023; Tsuda et al., 2023). A phase 2 clinical trial demonstrated that the time to initial symptoms after sunlight exposure was significantly increased by dersimelagon (Balwani et al., 2020). Another controlled phase 2 trial confirmed the efficacy of dersimelagon at increasing safe sunlight exposure time for both XLP and EPP patients (Balwani et al., 2023). Common adverse effects of dersimelagon include skin hyperpigmentation, nausea, headache, freckles, and ephelides (Balwani et al., 2020; Balwani et al., 2023).

6.2.2. Bitopertin

Currently, a phase 2 clinical trial of bitopertin for EPP treatment is in progress (Disc Medicine, 2022). Bitopertin selectively and potently inhibits GlyT1, the transporter supplies intracellular glycine for heme biosynthesis (Winter et al., 2016). In vitro studies showed that inhibition of GlyT1 decreased the total amount of PPIX synthesized and reduced the extent of PPIX-induced cytotoxicity and oxidative stress (Halloy et al., 2021). Bitopertin was also effective in reducing cholestasis and liver fibrosis in an EPP mouse model (Wu et al., 2022).

6.2.3. Gene therapy

Most EPP patients harbor a hypomorphic allele, which produces an unstable mRNA with a premature stop codon, resulting in reduced FECH activity (Gouya et al., 1999). Transfecting EPP patient-derived cells by an antisense oligonucleotide targeting this defective allele of FECH gene restored the activity of FECH, resulting in decreased PPIX levels (Oustric et al., 2014). With an aim to specifically target erythrocyte cells, a nanocomplex delivery system was recently developed combining this antisense oligonucleotide with bifunctional transferrin receptor 1 ligand-peptides, which showed the reduction of PPIX levels in the treated primary culture cells derived from the erythroid cells of an EPP patient (Erwin and Balwani, 2021; Mirmiran et al., 2019). Thus, this approach holds promise for future in vivo trials.

6.2.4. ABCG2 inhibitors

PPIX-induced phototoxicity was fully prevented in an EPP mouse model deficient in ABCG2 (Wang et al., 2019), leading to the hypothesis that ABCG2 inhibitors will suppress EPP and XLP associated phototoxicity. Deficiency of ABCG2 decreased PPIX distribution to the skin by trapping PPIX in erythrocytes, resulting in a lower level of PPIX in the plasma and less phototoxicity (Wang et al., 2019). In addition, deficiency of ABCG2 also trapped PPIX in hepatocytes and attenuated PPIX-induced cholestatic liver injury (Wang et al., 2019). Further studies are needed to evaluate the efficacy and safety of ABCG2 inhibitors for EPP and XLP therapy.

7. Summary and perspective

The current review summarized PPIX-induced phototoxicity as related to PPIX production and disposition, PPIX accumulation, symptoms, underlying mechanisms, and therapeutic approaches in EPP and XLP. PPIX accumulation stems from mutations of heme biosynthetic enzymes (ALAS2 and FECH) and is potentiated by additional factors such as ALAS inducers and FECH inhibitors. Accumulated PPIX in erythrocytes and plasma damages the skin in the presence of light by forming ROS. Endothelial cells in the skin are suggested to be the main target for PPIX phototoxicity. Individual differences in PPIX phototoxicity are significant, and may be caused by genetic differences, liver damage, chlorophyll derivatives, various drugs, and impaired antioxidant defense.

EPP and XLP patients who suffer from PPIX-induced phototoxicity have significantly diminished overall quality of life. Because EPP and XLP patients learn to avoid sunlight by limiting outdoor activities and wearing protective clothes, secondary effects develop to further threaten their health such as vitamin D deficiency, osteoporosis, social stress, and depression. Current approaches used to manage PPIX-induced phototoxicity include light-shielding, drugs that increase skin pigmentation, antioxidants, sunscreens, phototherapy, blood therapy, and bone marrow transplantation. Some novel potential approaches, such as GlyT1 inhibitors and ABCG2 inhibitors, have been proposed and are under further investigation.

Although understanding of the pathophysiology of PPIX-induced phototoxicity in EPP and XLP has advanced, the detailed mechanisms for such toxicity remain unclear, especially at the molecular level. Multiple therapeutic approaches have been used in EPP and XLP patients to manage PPIX-induced phototoxicity, but side effects and limitations of these available approaches have also been noted. Future research will better elucidate the molecular mechanisms of PPIX-induced phototoxicity as well as mechanism-based approaches to alleviate or eliminate phototoxic symptoms in EPP and XLP.

Acknowledgments

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126875), and in part by the National Institute of Allergy and Infectious Diseases (R01AI131983). Figures were created using BioRender.

Abbreviations:

ABCB6/10

ATP-binding cassette subfamily B member 6/10

ABCG2

ATP-binding cassette subfamily G member 2

ALA

δ-aminolevulinic acid

ALAS

ALA synthase

EPP

erythropoietic protoporphyria

FECH

ferrochelatase

MFRN1

mitoferrin 1

PPIX

protoporphyrin IX

ROS

reactive oxygen species

XLP

X-linked protoporphyria

Footnotes

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Declaration of Competing Interest

Xiaochao Ma and Junjie Zhu are inventors on a patent (WO2020236901) and hold equity in Portal Therapeutics, Inc. The authors declare no other competing interests.

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