Table 5.
Examples of the metabolic activation of physiological compounds by human cytochrome P450 enzymes.
| Compound | Enzyme | Subcategory | Reaction | PMIDs | References |
|---|---|---|---|---|---|
| Arachidonic acid | 2E1 | Fatty acid, polyunsaturated | Oxidation | 9169410, 14744237 | (Caro and Cederbaum 2004; Chen et al. 1997) |
| Arachidonic acid | 2W1 | Fatty acid, polyunsaturated | Epoxidation, epoxyeicosatrienoic acid (EET) formation, very low activity, if any, under physiological conditions | 26936974 | (Zhao et al. 2016) |
| Arachidonic acid | 2C8 | Fatty acid, polyunsaturated | Epoxidation, EET formation | 28701518, 7996455, 7625847, 15652503, 8651708, 7574697, 15766564, 11668219 | (Barbosa-Sicard et al. 2005; Dai et al. 2001b; Daikh et al. 1994; Fan and Roman 2017; Lundblad et al. 2005; Rifkind et al. 1995; Zeldin et al. 1995; Zeldin et al. 1996) |
| Arachidonic acid | 2C9 | Fatty acid, polyunsaturated | Epoxidation, EET formation, 14,15-, 11,12- and 8,9-EETs | 28701518, 7996455, 7625847, 8651708, 7574697, 15766564, 15652503 | (Barbosa-Sicard et al. 2005; Daikh et al. 1994; Fan and Roman 2017; Lundblad et al. 2005; Rifkind et al. 1995; Zeldin et al. 1995) |
| Arachidonic acid | 2J2 | Fatty acid, polyunsaturated | Epoxidation, EET formation | 28701518 | (Fan and Roman 2017) |
| Arachidonic acid | 4F3 | Fatty acid, polyunsaturated | Hydroxylation, 20-hydroxy eicosatetraenoic acid (HETE) formation, activation to pro-hypertensive activity | 28701518, 12709424 | (Christmas et al. 2003; Fan and Roman 2017) |
| Arachidonic acid | 4F2 | Fatty acid, polyunsaturated | Hydroxylation, 20-HETE formation, low activity, activation to pro-hypertensive activity | 9618440, 10660572, 28701518, 18662666 | (Fan and Roman 2017; Hirani et al. 2008; Lasker et al. 2000; Powell et al. 1998) |
| Arachidonic acid | 4A11 | Fatty acid, polyunsaturated | Hydroxylation, 20-HETE formation, activation to pro-hypertensive activity | 9618440, 10660572, 28701518 | (Fan and Roman 2017; Lasker et al. 2000; Powell et al. 1998) |
| Arachidonic acid | 1A2 | Fatty acid, polyunsaturated | Epoxidation, EET formation | 7625847, 15258110, 8651708, 7574697 | (Choudhary et al. 2004; Rifkind et al. 1995; Zeldin et al. 1995; Zeldin et al. 1996) |
| Arachidonic acid | 2E1 | Fatty acid, polyunsaturated | Hydroxylation, 20-HETE formation, activation to pro-hypertensive activity | 7625847 | (Rifkind, 1995) |
| Arachidonic acid | 2B6 | Fatty acid, polyunsaturated | Epoxidation, EET formation, activation, low activity | 7625847, 8651708, 7574697 | (Rifkind, 1995;Zeldin et al. 1996; Zeldin et al. 1995) |
| Arachidonic acid | 1A1 | Fatty acid, polyunsaturated | Epoxidation, EET formation | 15041462 | (Schwarz et al. 2004) |
| Arachidonic acid | 1B1 | Fatty acid, polyunsaturated | Epoxidation, EET formation | 15258110 | (Choudhary et al. 2004) |
| Arachidonic acid | 2C19 | Fatty acid, polyunsaturated | Epoxidation, EET formation | 9866708, 9435160 | (Bylund et al. 1998a; Bylund et al. 1998b) |
| 17β-Estradiol | 2D6 | Estrogen | C16α-Hydroxylation, minor reaction | 9667077, 9625734 | (Niwa et al. 1998; Yamazaki et al. 1998b) |
| 17β-Estradiol | 3A5 | Estrogen | C4-Hydroxylation, activation | 11454902, 15784278, 12865317, 12124305 | (Lee et al. 2003a; Lee et al. 2001; Williams et al. 2002; Zhu and Lee 2005) |
| 17β-Estradiol | 1B1 | Estrogen | C4-Hydroxylation, major extrahepatic enzyme, medium to low Km, medium activity, medium to low efficiency, activation | 8790407, 9498279, 9152602, 15784278, 12865317, 12902195, 10426814, 14703066, 10739169, 11465393, 10403516, 16112414, 12423652, 10862525, 10963622, 15142886, 11555828, 10910054, 11854143 11854439, 11719446, 25678418 | (Aklillu et al. 2002; Badawi et al. 2001; Chen et al. 2004; Chun et al. 2001; Hanna et al. 2000; Hayes et al. 1996; Jefcoate et al. 2000; Lee et al. 2003a; Li et al. 2000; Modugno et al. 2003; Niwa et al. 2015; Pang et al. 1999; Shimada et al. 1997b; Shimada et al. 2001b; Shimada et al. 1999; Spink et al. 2002a; Spink et al. 2002b; Spink et al. 1998; Tsuchiya et al. 2005; van Duursen et al. 2003; Watanabe et al. 2000; Zhu and Lee 2005) |
| 17β-Estradiol | 1A2 | Estrogen | C4-Hydroxylation, minor reaction, activation | 1449532, 15784278, 9625734, 9054608, 9667077, 9152602, 11555828, 12865317 | (Badawi et al. 2001; Kerlan et al. 1992; Lee et al. 2003a; Niwa et al. 1998; Shimada et al. 1997b; Shou et al. 1997; Yamazaki et al. 1998b; Zhu and Lee 2005) |
| 17β-Estradiol | 3A4 | Estrogen | C4-Hydroxylation, minor reaction, medium Km, medium activity, activation | 1449532, 11454902, 15784278, 9625734, 9054608, 9667077, 12865317, 12124305, 11555828, 9003190 | (Badawi et al. 2001; Kerlan et al. 1992; Lee et al. 2003a; Lee et al. 2001; Niwa et al. 1998; Shou et al. 1997; Ueng et al. 1997; Williams et al. 2002; Yamazaki et al. 1998b; Zhu and Lee 2005) |
| 17β-Estradiol | 1A2 | Estrogen | C16α-Hydroxylation (major enzyme, high Km, low activity) | 9625734, 9054608, 12865317, 9667077, 11555828 | (Badawi et al. 2001; Lee et al. 2003a; Niwa et al. 1998; Shou et al. 1997; Yamazaki et al. 1998b) |
| 17β-Estradiol | 1B1 | Estrogen | C16α-Hydroxylation,(minor enzyme, medium and high Km, low activity) | 9667077, 11555828, 11854439, 10910054 | (Aklillu et al. 2002; Badawi et al. 2001; Hanna et al. 2000; Niwa et al. 1998) |
| 17β-Estradiol | 1A1 | Estrogen | C16α-Hydroxylation (high Km, low activity) | 9667077, 11555828, 12865317, 15784278, 10403516 | (Badawi et al. 2001; Lee et al. 2003a; Niwa et al. 1998; Pang et al. 1999; Zhu and Lee 2005) |
| 17β-Estradiol | 1A1 | Estrogen | C4-Hydroxylation (minor reaction, medium Km, medium efficiency, low activity, activation) | 8790407, 11555828, 12865317, 15784278, 10403516, 25678418 | (Badawi et al. 2001; Hayes et al. 1996; Lee et al. 2003a; Niwa et al. 2015; Pang et al. 1999; Zhu and Lee 2005) |
| 17β-Estradiol | 2A6 | Estrogen | C4-Hydroxylation (low activity, activation) | 12865317, 15784278 | (Lee et al. 2003a; Zhu and Lee 2005) |
| 17β-Estradiol | 2C19 | Estrogen | C4-Hydroxylation (low activity, activation) | 11067738 | (Satoh et al. 2000) |
| 17β-Estradiol | 2C19 | Estrogen | C16α-Hydroxylation (low activity) | 9667077, 9625734, 15784278 | (Niwa et al. 1998; Yamazaki et al. 1998b; Zhu and Lee 2005) |
| 17β-Estradiol | 2C8 | Estrogen | C4-Hydroxylation (low activity, activation) | 12865317, 11067738 | (Lee et al. 2003a; Satoh et al. 2000) |
| 17β-Estradiol | 2C9 | Estrogen | C4-Hydroxylation (very low activity, activation) | 9625734, 12865317, 15784278 | (Lee et al. 2003a; Yamazaki et al. 1998b; Zhu and Lee 2005) |
| 17β-Estradiol | 2C9 | Estrogen | C16α-Hydroxylation (minor reaction, low activity) | 9667077, 9625734, 15784278 | (Niwa et al. 1998; Yamazaki et al. 1998b; Zhu and Lee 2005) |
| 17β-Estradiol | 2D6 | Estrogen | C4-Hydroxylation (very low activity, activation) | 11067738 | (Satoh et al. 2000) |
| 17β-Estradiol | 3A4 | Estrogen | C16α-Hydroxylation, high Km, low activity | 9625734, 11454902, 12865317, 14559847, 9667077, 14703066, 11555828 | (Badawi et al. 2001; Lee et al. 2003a; Lee et al. 2003b; Lee et al. 2001; Modugno et al. 2003; Niwa et al. 1998; Yamazaki et al. 1998b) |
| 17β-Estradiol | 3A5 | Estrogen | C16α-Hydroxylation, high Km, low activity | 12865317, 14559847 | (Lee et al. 2003a; Lee et al. 2003b) |
| 17β-Estradiol | 3A7 | Estrogen | C4-Hydroxylation, high Km, low activity, activation | 14559847 | (Lee et al. 2003b) |
| 17β-Estradiol | 3A4 | Estrogen | C2-Hydroxylation, activation, major enzyme in liver | 11454902, 11067738, 14703066, 12865317, 11555828, 16112414 | (Badawi et al. 2001; Lee et al. 2003a; Lee et al. 2001; Modugno et al. 2003; Satoh et al. 2000; Tsuchiya et al. 2005) |
| 17β-Estradiol | 3A5 | Estrogen | C2-Hydroxylation, activation | 11454902, 12865317 | (Lee et al. 2003a; Lee et al. 2001) |
| 17β-Estradiol | 2D6 | Estrogen | C2-Hydroxylation, activation | 12865317 | (Lee et al. 2003a) |
| 17β-Estradiol | 1A1 | Estrogen | C15α-Hydroxylation | 12865317 | (Lee et al. 2003a) |
| 17β-Estradiol | 1A1 | Estrogen | C6α-Hydroxylation, | 12865317 | (Lee et al. 2003a) |
| 17β-Estradiol | 1A1 | Estrogen | C7α-Hydroxylation | 12865317 | (Lee et al. 2003a) |
| 17β-Estradiol | 1B1 | Estrogen | C2-Hydroxylation, low Km and low activity, activation | 8790407, 12865317, 11555828, 25678418 | (Badawi et al. 2001; Hayes et al. 1996; Lee et al. 2003a; Niwa et al. 2015) |
| 17β-Estradiol | 3A4 | Estrogen | C16β-Hydroxylation, low activity | 12865317, 14703066 | (Lee et al. 2003a; Modugno et al. 2003) |
| 17β-Estradiol | 1A2 | Estrogen | C2-Hydroxylation, high activity, activation, major enzyme in liver | 12865317, 11555828, 16112414 | (Badawi et al. 2001; Lee et al. 2003a; Tsuchiya et al. 2005) |
| 17β-Estradiol | 1A1 | Estrogen | C2-Hydroxylation, high activity, major extrahepatic enzyme, activation | 8790407, 9498279, 11854143, 12902195, 14703066, 16112414, 15142886, 25678418 | (Chen et al. 2004; Hayes et al. 1996; Modugno et al. 2003; Niwa et al. 2015; Spink et al. 2002b; Spink et al. 1998; Tsuchiya et al. 2005; van Duursen et al. 2003) |
| 17β-Estradiol | 2W1 | Estrogen | C2-Hydroxylation, very low activity under physiological conditions, activation | 26936974 | (Zhao et al. 2016) |
| 17β-Estradiol | 2A6 | Estrogen | C2-Hydroxylation, activation | 12865317 | (Lee et al. 2003a) |
| 17β-Estradiol | 2B6 | Estrogen | C2-Hydroxylation, activation | 12865317 | (Lee et al. 2003a) |
| 17β-Estradiol | 2C8 | Estrogen | C2-Hydroxylation, activation | 12865317 | (Lee et al. 2003a) |
| 17β-Estradiol | 2C9 | Estrogen | C2-Hydroxylation, activation | 12865317 | (Lee et al. 2003a) |
| 17β-Estradiol | 2C19 | Estrogen | C2-Hydroxylation, activation | 12865317 | (Lee et al. 2003a) |
| 17β-Estradiol | P450 2E1 | Estrogen | C4-Hydroxylation (low activity, activation) | 11067738, 15784278 | (Satoh et al. 2000; Zhu and Lee 2005) |
| 17β-Estradiol | 3A7 | Estrogen | C16α-Hydroxylation, very low activity | 12865317, 14559847 | (Lee et al. 2003a; Lee et al. 2003b) |
| Estrone | 1A1 | Estrogen | C15α-Hydroxylation, high activity | 12865317, 15784278 | (Lee et al. 2003a; Zhu and Lee 2005) |
| Estrone | 2A6 | Estrogen | C16α-Hydroxylation, at higher concentration | 9635876 | (Huang et al. 1998) |
| Estrone | 3A7 | Estrogen | C16α-Hydroxylation, minor reaction | 12865317, 14559847 | (Lee et al. 2003a; Lee et al. 2003b) |
| Estrone | 1A1 | Estrogen | C16α-Hydroxylation, minor reaction | 9635876, 15784278, 16537715 | (Cribb et al. 2006; Huang et al. 1998; Zhu and Lee 2005) |
| Estrone | 1B1 | Estrogen | C4-Hydroxylation, low Km, major reaction, activation | 9152602, 15784278, 12865317, 16537715, 10426814, 10739169, 11465393, 16207128, 25678418 | (Cribb et al. 2006; Lee et al. 2003a; Niwa et al. 2015; Paracchini et al. 2005; Shimada et al. 1997b; Shimada et al. 2001b; Shimada et al. 1999; Watanabe et al. 2000; Zhu and Lee 2005) |
| Estrone | 1A1 | Estrogen | C4-Hydroxylation, medium activity, activation | 12865317, 15784278, 16537715, 25678418 | (Cribb et al. 2006; Lee et al. 2003a; Niwa et al. 2015; Zhu and Lee 2005) |
| Estrone | 1A1 | Estrogen | C7α-Hydroxylation, minor reaction, activation | 12865317, 15784278 | (Lee et al. 2003a; Zhu and Lee 2005) |
| Estrone | 1A2 | Estrogen | C4-Hydroxylation (medium Km, very low to medium activity, activation) | 9625734, 9054608, 12865317, 15784278, 16537715 | (Cribb et al. 2006; Lee et al. 2003a; Shou et al. 1997; Yamazaki et al. 1998b; Zhu and Lee 2005) |
| Estrone | 1A2 | Estrogen | C16α-Hydroxylation (minor reaction, very low activity, activation) | 9625734, 9054608, 12865317, 25678418 | (Lee et al. 2003a; Niwa et al. 2015; Shou et al. 1997; Yamazaki et al. 1998b) |
| Estrone | 3A7 | Estrogen | C4-Hydroxylation (low activity, medium Km, activation) | 12865317, 14559847 | (Lee et al. 2003a; Lee et al. 2003b) |
| Estrone | 3A7 | Estrogen | C2-Hydroxylation (low activity, activation) | 14559847 | (Lee et al. 2003b) |
| Estrone | 3A5 | Estrogen | C16α-Hydroxylation (high Km, low activity) | 9635876, 9625734, 9054608, 12865317, 9667077, 15784278, 16537715, 14559847 | (Cribb et al. 2006; Huang et al. 1998; Lee et al. 2003a; Lee et al. 2003b; Niwa et al. 1998; Shou et al. 1997; Yamazaki et al. 1998b; Zhu and Lee 2005) |
| Estrone | 2C9 | Estrogen | C16α-Hydroxylation (low activity, activation) | 9635876, 9625734, 9054608, 14703066, 9667077, 15784278 | (Huang et al. 1998; Modugno et al. 2003; Niwa et al. 1998; Shou et al. 1997; Yamazaki et al. 1998b; Zhu and Lee 2005) |
| Estrone | 3A4 | Estrogen | C16α-Hydroxylation (high Km, low activity, major enzyme) | 9625734, 9054608, 9667077, 9635876, 12865317, 15784278, 14559847, 25678418 | (Huang et al. 1998; Lee et al. 2003a; Lee et al. 2003b; Niwa et al. 2015; Niwa et al. 1998; Shou et al. 1997; Yamazaki et al. 1998b; Zhu and Lee 2005) |
| Estrone | 3A4 | Estrogen | C4-Hydroxylation (high Km, low activity, major enzyme, activation) | 9635876, 9625734, 9054608, 9667077, 12865317, 15784278 | (Huang et al. 1998; Lee et al. 2003a; Niwa et al. 1998; Shou et al. 1997; Yamazaki et al. 1998b; Zhu and Lee 2005) |
| Estrone | 2C9 | Estrogen | C4-Hydroxylation, (very low activity, activation) | 9625734, 12865317, 15784278 | (Lee et al. 2003a; Yamazaki et al. 1998b; Zhu and Lee 2005) |
| Estrone | 2C19 | Estrogen | C16α-Hydroxylation (low activity) | 9054608, 9625734, 15784278, 16537715 | (Cribb et al. 2006; Shou et al. 1997; Yamazaki et al. 1998b; Zhu and Lee 2005) |
| Estrone | 2E1 | Estrogen | C16α-Hydroxylation (very low activity) | 9054608, 9625734, 15784278 | (Shou et al. 1997; Yamazaki et al. 1998b; Zhu and Lee 2005) |
| Estrone | 2B6 | Estrogen | C4-Hydroxylation (very low activity, activation) | 9054608, 9625734, 15784278 | (Shou et al. 1997; Yamazaki et al. 1998b; Zhu and Lee 2005) |
| Estrone | 2E1 | Estrogen | C4-Hydroxylation (very low activity, activation) | 9054608, 9625734, 15784278 | (Shou et al. 1997; Yamazaki et al. 1998b; Zhu and Lee 2005) |
| Estrone | 2C8 | Estrogen | C-4 Hydroxylation (very low activity, activation) | 9054608, 9625734 | (Shou et al. 1997; Yamazaki et al. 1998b) |
| Estrone | 1A1 | Estrogen | C6α-Hydroxylation, low activity | 12865317 | (Lee et al. 2003a) |
| Estrone | 1A1 | Estrogen | C2-Hydroxylation, major metabolite, activation | 12865317, 25678418 | (Lee et al. 2003a; Niwa et al. 2015) |
| Estrone | 1A2 | Estrogen | C2-Hydroxylation, high activity, activation | 12865317 | (Lee et al. 2003a) |
| Estrone | 1B1 | Estrogen | C2-Hydroxylation, low activity, activation | 12865317, 25678418 | (Lee et al. 2003a; Niwa et al. 2015) |
| Estrone | 3A4 | Estrogen | C2-Hydroxylation, activation | 12865317, 25678418 | (Lee et al. 2003a; Niwa et al. 2015) |
| Estrone | 3A5 | Estrogen | C2-Hydroxylation, activation | 12865317 | (Lee et al. 2003a) |
| Estrone | 3A5 | Estrogen | C4-Hydroxylation, activation | 12865317 | (Lee et al. 2003a) |