CYP3A4

CYP3A4 (CYP3A4 stands for Cytochrome P450 Family 3 Subfamily A Member 4/the original name was "CYP3A3") is an enzyme is a monooxygenase, a member of the cytochrome P450 superfamily of enzymes. The enzyme is encoded by the gene of the same name located on chromosome 7q21.1.

The cytochrome P450 proteins are monooxygenasesthat catalyze many reactions involved in drug metabolism and the synthesis of cholesterol, steroids and other lipids. The encoded CYP3A4 protein is localized in the endoplasmic reticulum. Its expression is induced by glucocorticoids and some pharmacological agents. The cytochrome P450 enzyme is involved in the metabolism of about half of the drugs used today, including acetaminophen, codeine, cyclosporin A, diazepam, erythromycin and chloroquine. The enzyme also metabolizes some steroids and carcinogens. Mechanistically, molecular oxygen is used by inserting one oxygen atom into a substrate and reducing the second to a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH hemoprotein reductase).

The cytochrome P450 enzyme catalyzes the hydroxylation of carbon-hydrogen bonds (Lee AJ et al. 2003).

Exhibits high catalytic activity in 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 the oxidative deactivation of testosterone (Choi MH et al. (2005) Characterization of testosterone 11 beta-hydroxylation catalyzed by human liver microsomal cytochromes P450. Drug Metab Dispos 33:714-718.

Metabolizes testosterone to biologically less active 2beta- and 6beta-hydroxytestosterones (Choi MH et al. 2005).

Contributes to the formation of hydroxycholesterols (oxysterols), in particular A-ring-hydroxylated cholesterol at the C-4beta position and side-chain-hydroxylated cholesterol at the C-25 position, which probably contributes to cholesterol degradation and bile acid biosynthesis (Honda A et al. 2011).

Catalyzes the hydroxylation of polyunsaturated fatty acids (PUFA).

Metabolizes the endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12- and 14,15-epoxyecosatrienoic acid ethanolamides (EpETrE-EAs), possibly modulating the signaling of the endocannabinoid system (Pratt-Hyatt M et al. 2010).

Plays a role in the metabolism of retinoids. Exhibits high catalytic activity in the oxidation of all-trans-retinol to all-trans-retinal, a rate-determining step in the biosynthesis of all-trans-retinoic acid (atRA). Metabolizes atRA further to 4-hydroxyretinoate and may play a role in hepatic atRA clearance.

Is responsible for the oxidative metabolism of xenobiotics.

Acts as a 2-exo-monooxygenase for the plant lipid 1,8-cineole (eucalyptol). Acts as a 1,4-cineole 2-exo-monooxygenase (Miyazawa M et al. 2001).

Metabolizes the majority of administered drugs.

Catalyzes the sulfoxidation of the anthelmintics albendazole and fenbendazole.

Hydroxylates the antimalarial drug quinine.

Is also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (Roizen JD et al. 2018).

1. Aoyama T et al. (1989) 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 264:10388-10395
2. Badawi AF et al. (2001) Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol. Metabolism 50:1001-10033.
3. Chen H et al. (2000) Biosynthesis of all-trans-retinoic acid from all-trans-retinol: catalysis of all-trans-retinol oxidation by human P-450 cytochromes. Drug Metab Dispos 28:315-322.
4. Choi MH et al. (2005) Characterization of testosterone 11 beta-hydroxylation catalyzed by human liver microsomal cytochromes P450. Drug Metab Dispos 33:714-718.
5. Honda A et al. (2011) Cholesterol 25-hydroxylation activity of CYP3A. J Lipid Res 52:1509-16).
6. Lee AJ et al. (2003) Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology 144:3382-3398
7. Miyazawa M et alk. (2001) 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 29:200-205).
8. Pratt-Hyatt M et al. (2010) Effects of a commonly occurring genetic polymorphism of human CYP3A4 (I118V) on the metabolism of anandamide. Drug Metab Dispos 38:2075-2082.
9. Roizen JD et al. (2018) CYP3A4 mutation causes vitamin D-dependent rickets type 3. J Clin Invest 128:1913-1918.