Role of cytochrome P450 in estradiol metabolism in vitro.
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Cheng ZN, Shu Y, Liu ZQ, Wang LS, Ou-Yang DS, Zhou HH
Role of cytochrome P450 in estradiol metabolism in vitro.
Acta Pharmacol Sin. 2001 Feb;22(2):148-54.
- PubMed ID
- 11741520 [ View in PubMed]
- Abstract
AIM: Catechol estrogens and 16alpha-hydroxy estrogen are important metabolites that cause carcinogenesis. This study was aimed to stud y the role of cytochrome P450 in estradiol metabolism. METHODS: The estradiol metabolites were determined with HPLC-ECD. Correlation of estradiol metabolites production between cytochrome P450 activity, the inhibitory effect of specific inhibitors and enzyme catalyzing kinetics were studied in cDNA-expressed P450 or human liver microsomes. RESULT: CYP1A2, CYP3A4, and CYP2C9 catalyze the estradiol 2-hydroxylation. CYP2C9, CYP2C19, and CYP2C8 have high activity in catalyzing 17beta-hydroxy dehydrogenation in cDNA expressed P450, but CYP1A2 is the most important enzyme in catalyzing estradiol 2-hydroxylation. Using furafyllin and troleandomycin to inhibit CYP1A2 and CYP3A4 in liver microsomes, it was found that the 2-hydroxylation had been inhibited about the same amount. This result suggests that in human liver microsomes CYP1A2 and CYP3A4 play an important role in 2-hydroxy estradiol formation. At low substrate concentration, 17beta -hydroxy dehydrogenation dominated the estradiol metabolism, but at high substrate concentration, 2-hydroxylation exceeded 17beta-hydroxy dehydrogenation to become the important mechanism. CONCLUSION: CYP1A2 and CYP3A4 are two important enzymes catalyzing the main estradiol 2-hydroxylation metabolism pathway at high substrate concentrations. 17beta-hydroxy dehydrogenation is the main metabolism pathway at low concentrations, and CYP2C9, CYP2C19, and CYP2C8 may have high catalyzing activity.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Estradiol Cytochrome P450 2C19 Protein Humans UnknownSubstrateDetails Estradiol Cytochrome P450 2C8 Protein Humans UnknownSubstrateDetails Estradiol Cytochrome P450 2C9 Protein Humans UnknownSubstrateDetails Estradiol Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails Estradiol acetate Cytochrome P450 1A2 Protein Humans UnknownSubstrateInhibitorDetails Estradiol acetate Cytochrome P450 2C19 Protein Humans UnknownSubstrateDetails Estradiol acetate Cytochrome P450 2C8 Protein Humans UnknownSubstrateDetails Estradiol cypionate Cytochrome P450 2C19 Protein Humans UnknownSubstrateDetails Estradiol cypionate Cytochrome P450 2C8 Protein Humans UnknownSubstrateDetails Estradiol valerate Cytochrome P450 2C19 Protein Humans UnknownSubstrateDetails Estradiol valerate Cytochrome P450 2C8 Protein Humans UnknownSubstrateDetails