Estradiol metabolism. Endogenous and exogenous estrogens undergo oxidative metabolism by hepatic microsomalcytochrome P-450. Aromatic hydroxylation at either the C2 or C4 position is a major routeof Estradiol metabolism in humans and other mammals, although there is less4-hydroxylation than 2-hydroxylation. Several cytochrome P450 isoforms including Cytochrome P450, family 2, subfamily C,polypeptides 8 ( CYP2C8 )  and 9 ( CYP2C9 ) , Cytochrome P450, family 3, subfamily A, polypeptides 4 ( CYP3A4 ) and 5 ( CYP3A5 ) , Cytochrome P450, family 2,subfamily D, polypeptide 6 ( CYP2D6 ) , Cytochrome P450, family 1,subfamily A, polypeptides 1 ( CYP1A1 )  and 2 ( CYP1A2 ), Cytochrome P450, family 1, subfamily B, polypeptide 1 ( CYP1B1 ) and Cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19 )  were shown to catalyze hydroxylation ofEstradiol to 2-Hydroxyestradiol or/and 4-Hydroxyestradiol.Furthermore, Catechol-O-methyltransferase ( COMT ) catalyzes the methylation of2-Hydroxyestradiol and 4-Hydroxyestradiol to 2-Methoxyestradiol and4-Metoxyestradiol, respectively . Cytochrome 450 isoforms CYP1A2 and CYP3A4 catalyzes the16alpha-hydroxylation of Estradiol forming Estriol .Estriol is glucuronidated to Estriol 16-D-glucuronoside by UDPglucuronosyltransferase 2 family, polypeptide B11 ( UGT2B11 ) . Other pathways of Estradiol metabolism include formation of glucuronideconjugates and sulfation. UDP glucuronosyltransferase 1 family, polypeptides A1 (UGT1A1 )  and A10 ( UGT1A10 ) , and UDPglucuronosyltransferase 2 family, polypeptide B28 ( UGT2B28 ) convert Estradiol to Estradiol 3-glucuronide. Several sulfotransferases including Sulfotransferase family, cytosolic, 1A,phenol-preferring, members 1 ( SULT1A1 )  and 3 ( SULT1A3 ), Sulfotransferase family 1E, estrogen-preferring, member 1 (SULT1E1 )  and Sulfotransferase family, cytosolic, 2A,dehydroepiandrosterone (DHEA)-preferring, member 1 ( SULT2A1 ) catalyze sulfation of Estradiol to 17beta-Estra-1,3,5-trien-3,17-diol3-sulfate.