Role of cytochrome P450 in estradiol metabolism in vitro.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Cheng
Z N
ZN
Pharmacogenetics Research Institute, Hunan Medical University, Changsha 410 078, China.
Shu
Y
Y
Liu
Z Q
ZQ
Wang
L S
LS
Ou-Yang
D S
DS
Zhou
H H
HH
D000328:Adult; D019388:Cytochrome P-450 CYP1A2 / Q000502:physiology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*
D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; C001390:2-hydroxyestradiol; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human