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Cytochrome P450 3A4

Definition:

A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds. Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position. Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone. Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones. Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis. Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond. Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling. Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance. Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole. Hydroxylates antimalarial drug quinine. Acts as a 1,4-cineole 2-exo-monooxygenase. Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)).

References:

[1]. T Aoyama, et al. Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. J Biol Chem. 1989 Jun 25;264(18):10388-95. [Content Brief]

[2]. Akira Honda, et al. Cholesterol 25-hydroxylation activity of CYP3A. J Lipid Res. 2011 Aug;52(8):1509-16. [Content Brief]

[3]. Joel A Krauser, et al. Testosterone 1 beta-hydroxylation by human cytochrome P450 3A4. Eur J Biochem. 2004 Oct;271(19):3962-9. [Content Brief]

[4]. Jeffrey D Roizen, et al. CYP3A4 mutation causes vitamin D-dependent rickets type 3. J Clin Invest. 2018 May 1;128(5):1913-1918. [Content Brief]

[5]. Qian Cheng, et al. Oxidation of dihydrotestosterone by human cytochromes P450 19A1 and 3A4. J Biol Chem. 2012 Aug 24;287(35):29554-67. [Content Brief]

[6]. A F Badawi, et al. Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol. Metabolism. 2001 Sep;50(9):1001-3. [Content Brief]

[7]. Danièle Lucas, et al. Stereoselective epoxidation of the last double bond of polyunsaturated fatty acids by human cytochromes P450. J Lipid Res. 2010 May;51(5):1125-33. [Content Brief]

[8]. Man Ho Choi, et al. Characterization of testosterone 11 beta-hydroxylation catalyzed by human liver microsomal cytochromes P450. Drug Metab Dispos. 2005 Jun;33(6):714-8. [Content Brief]

[9]. J Marill, et al. Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolites. Mol Pharmacol. 2000 Dec;58(6):1341-8. [Content Brief]

[10]. Matthew Pratt-Hyatt, et al. Effects of a commonly occurring genetic polymorphism of human CYP3A4 (I118V) on the metabolism of anandamide. Drug Metab Dispos. 2010 Nov;38(11):2075-82. [Content Brief]

[11]. H Chen, et al. Biosynthesis of all-trans-retinoic acid from all-trans-retinol: catalysis of all-trans-retinol oxidation by human P-450 cytochromes. Drug Metab Dispos. 2000 Mar;28(3):315-22. [Content Brief]

[12]. Anthony J Lee, et al. Human cytochrome P450 3A7 has a distinct high catalytic activity for the 16alpha-hydroxylation of estrone but not 17beta-estradiol. Cancer Res. 2003 Oct 1;63(19):6532-6. [Content Brief]

[13]. M Miyazawa, et al. Roles of cytochrome P450 3A enzymes in the 2-hydroxylation of 1,4-cineole, a monoterpene cyclic ether, by rat and human liver microsomes. Xenobiotica. 2001 Oct;31(10):713-23. [Content Brief]

[14]. C-C Peng, et al. Evaluation of 6β-hydroxycortisol, 6β-hydroxycortisone, and a combination of the two as endogenous probes for inhibition of CYP3A4 in vivo. Clin Pharmacol Ther. 2011 Jun;89(6):888-95. [Content Brief]

[15]. H C Rawden, et al. Relative contribution of cytochromes P-450 and flavin-containing monoxygenases to the metabolism of albendazole by human liver microsomes. Br J Clin Pharmacol. 2000 Apr;49(4):313-22. [Content Brief]

[16]. Anthony J Lee, et al. Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology. 2003 Aug;144(8):3382-98. [Content Brief]

[17]. M Miyazawa, et al. Oxidation of 1,8-cineole, the monoterpene cyclic ether originated from eucalyptus polybractea, by cytochrome P450 3A enzymes in rat and human liver microsomes. Drug Metab Dispos. 2001 Feb;29(2):200-5. [Content Brief]

[18]. X J Zhao, et al. Identification of human cytochrome P450 isoforms involved in the 3-hydroxylation of quinine by human live microsomes and nine recombinant human cytochromes P450. J Pharmacol Exp Ther. 1996 Dec;279(3):1327-34. [Content Brief]

[19]. J Bylund, et al. Cytochromes P450 with bisallylic hydroxylation activity on arachidonic and linoleic acids studied with human recombinant enzymes and with human and rat liver microsomes. J Pharmacol Exp Ther. 1998 Jan;284(1):51-60. [Content Brief]

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