Table 1.

Effect of N-acetylcysteine (NAC) in experimental colitis and inflammatory bowel disease randomized clinical studies.

Author	Inflammatory bowel disease study	NAC effect
		Colon	Liver	Kidney	Others
Animal model
Ardite et al. [51]	Animals: male sprague-dawley rats weighing 200–250 g; C.i.: 30 mg of TNBS—once; NAC treatment: 40 nM (water (w/v)) for 4 hr after c.i.	↑ Mucosal GSH levels; improved histologic score	NT	NT	NT
Nosál'ová et al. [52]	Animals: wistar rats; C.i.: 4% (v/v) acetic acid (i.r.), once; NAC treatment: 20, 40, 100, or 200 mg (i.r.), before c.i., 100 mg (i.r.) after c.i.	NT	NT	NT	Pretreatment: prevented weight loss (dose-dependently)
Seril et al. [53]	Animals: C57BL/6J mice; C.i.: 0.7% DSS water (w/v)/7 days, for 12 cycles: 7 days DSS—10 days water free; NAC treatment: 2x/day–0.2%/day (∼200 mg/kg) NAC in diet (45 mg iron/kg add in AIN76A diet) during all cycles of c.i.	↓ UC index; ↑ apoptosis; did not alter inflammatory cells	NT	NT	Did not alter weight body
Akgun et al. [5]	Animals: swiss rats; C.i.: 4% (v/v) acetic acid (i.r.), once; NAC treatment: 20 mg/kg and 100 mg/kg (i.r and/or i.p.), for 2 or 7 days	NAC 100 mg/day for 7 days: ↓ inflammation (MPO levels) and nitrosative stress (↓iNOS); did not improve GSH levels	NT	NT	NT
Kurutas et al. [55]	Animals: wistar rats; C.i.: 4% (v/v) acetic acid (i.r), once; NAC pretreatment: 500 mg/kg/day (i.p.), 1 hr before c.i.	↓ MPO activity; normalized SOD activity	NT	NT	NT
Cetinkaya et al. [56]	Animals: wistar rats; C.i.: 4% (v/v) acetic acid (i.r.), once; NAC pretreatment and treatment: 500 mg/kg (i.p. or i.r.), 1 hr before c.i. or 24 hr after c.i.	NAC 1 hr before c.i.: prevented the reduction of antioxidant defense (↑ GSH levels). NAC 24 hr after c.i.: ↓ macroscopic damage (NAC i.r. and i.p.); ↓ inflammation (MPO acitvity; NAC i.r. and i.p.); ↓ oxidative damage (MDA levels); prevented the reduction of antioxidant defense (↑ GSH levels - mainly NAC i.r. –, SOD and CAT activity)	NT	NT	NT
Damiani et al. [57]	Animals: wistar rats; C.i. 50 g/L of DSS in water/5 days; NAC treatment: 20 mg/kg (s.c.), 2x/day, during c.i.	Did not prevent macroscopic lesion score; prevent macroscopic damage; did not prevent oxidative damage (TBARS level)	NT	NT	↑ Leukocytosis
Gommeaux et al. [58]	Animals: TP53INP1-deficient mice and WT mice; C.i.: 3.5% DSS water (w/v)/7 days; NAC pretreatment and treatment: 10 mg/mL (water (w/v)) for 10 days before, during, and after c.i.	NT	NT	NT	Delayed diarrhea and rectal bleeding (TP53INP1 -deficient mice and WT mice); no change in the weight loss and mortality; inhibit tumorigenesis (WT mice)
You et al. [59]	Animals: balb/c mice; C.i.: 5% DSS water (w/v)/7 days; NAC treatment: 0.3 mL NAC (i.r.), during c.i.	Improved colon shortening; ↓ DAI score; ↓ histologic score; ↓ inflammation (↓ MPO activity, IL-1β and TNF-α levels); ↓ oxidative damage (↓ ROS and MDA levels, and ↑ paraoxonase 1 and GSH activities)	NT	NT	Improved ↓ weight body
Amrouche-Mekkioui and Djerdjouri [40]	Animals: NMRI mice; C.i.: 5% DSS water (w/v), for 3 cycles: 5 days DSS—10 days water free; NAC treatment: 150 mg/kg (water) during all cycles of c.i.	Improved: ulcerative colitis score, histological score, clinical response, and mucosa thickness; ↓ inflammation (MPO activity) and oxidative damage (MDA and protein carbonyl levels, and iNOS activity); ↑ antioxidant defense (CAT and GSH activity); prevented mitochondrial dysfunction	NT	NT	NT
Uraz et al. [60]	Animals: wistar rats; C.i.: 4% (v/v) acetic acid/3 days (i.r); NAC treatment: 500 mg/kg/day (i.r), 5 min after c.i.	Prevented increased of wet weight; ↓ macroscopic and microscopic lesion scores; ↓ inflammatory activity (↓ MPO, IL-1β, IL-6, and TNF-α); prevented oxidative damage (↓TBARS); ↑ antioxidant defense (SOD and GSH);	NT	NT	NT
Kim et al. [31]	Animals: C57BL/6 WT and GPx1−/− × Cat−/− mice; C.i.: 3% (w/v) DSS water for 12 hr in a day/4 days; NAC pretreatment and treatment: 40 mM (gavage) for 3 days before c.i. and for 4 days during c.i.	Worst colon shortening (GPx1−/− × Cat−/− mice); promoted severe inflammatory changes and expression of pY-Stat3 (WT mice)	NT	NT	Promoted severe weight loss (GPx1−/− × Cat−/− mice).
Moura el al. [41]	Animals: wistar rats; C.i.: 2% DSS water (w/v)/5 days; NAC pretreatment and treatment: 100 mg/kg (diet), for 7 days before c.i. and during c.i.	Prevented histologic damage; normalized oxidative damage (H2O2, MDA, and GSH levels); did not alter inflammation (TNF-α, INF-γ and IL-10)	Did not alter weight body, oxidative damage, antioxidant defense or inflammation	NT	Prevented anemia and leukocytosis
Cha et al. [61]	Animals: C57BL/6 WT IDH2+/+ and knockout IDH2−/− mice; C.i.: 2% DSS water (w/v)/7 days; NAC pretreatment and treatment: 100 mg/kg (i.p.) for 3 days before, and during c.i.	Prevented colon shortening; improved histologic score; improved apoptosis; ↑ NF-κB	NT	NT	NT
Shi et al. [62]	Animals: C57BL/6 mice; C.i.: 3% DSS water (w/v)/7 days; NAC treatment: 2 mg/kg (gavage), during c.i.	↓ DAI score; prevented colon shortening; improved histologic score; prevented oxidative damage (↓ MDA and ROS); normalized GPx activity; ↓ inflammation (↓ IL-1β, IL-6, MCP-1, and TNF-α)	No change was observed (AST and ALT–normal serum levels)	No change was observed (creatinine–normal serum levels)	↑ Body weight
Wang et al. [63]	Animals: C57BL/6N mice; C.i.: 3% DSS water (w/v)/7 days + HFCS; NAC pretreatment and treatment: 250 mg/kg (gavage), during c.i.	Prevented colon shortening	NT	NT	Prevented weight loss; ↓ inflammation (TNF-α, IL-6, and IL-1β serum levels)
Human studies
Guijarro et al. [16]	Type of study: randomized, placebo-controlled pilot study; patients: 37 UC patients (18–70 years); NAC treatment: 2.4 g/day/4 weeks plus mesalamine				↓ Inflammation (serum IL-8 and MCP-1 levels)
Shirazi et al. [17]	Type of study: a randomized, double-blind controlled clinical trial; patients: 169 UC patients (18–75 years); NAC treatment: 400 mg–2x/day/16 weeks plus mesalamine	↓ Frequency of endoscopic relapse			↓ Inflammation (↓ fecal calprotectin, serum ESR, and hs-CRP levels)

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CAT, catalase; c.i., colitis induction; DAI, disease activity index; DSS, dextran sulfate sodium; ESR, erythrocyte sedimentation rate; GPx, glutathione peroxidase; GSH, glutathione reduced; HFCS, high-fructose cornsyrup; hs-CRP, high-sensitive C-reactive protein; IDH, mitochondrial NADP+-dependent isocitrate dehydrogenase; IL, interleukin; INF-γ, interferon gamma; i.p., intraperitoneal; i.r., intrarectal; MCP-1, monocyte chemotactic protein 1; MPO, myeloperoxidase; NF-κB, factor nuclear kappa B; pY-Stat3, anti-phosphotyrosine -Stat3; ROS, reactive oxygen species; TBARS, thiobarbituric acid reactive species; TNBS, 2,4,6-trinitrobenzenesulfonic acid; TNF-α, tumor necrosis factor; TP53INP1, tumor protein 53-induced nuclear protein 1; UC, ulcerative colitis; UC index (lesion severity, ulceration, hyperplasia, area of inflammatory involvement, and total histological score); v, volume; w, weight; WT, wild type.