Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol.
The steady-state kinetics and specific activity of 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol (E(2)) were evaluated for human cytochrome P450 (CYP) 1A1, 1A2, 1B1, and 3A4 enzymes, using complementary DNA-expressed CYP isoforms. CYP1A2 showed the highest 2-hydroxylation activity, followed by CYP1A1, 1B1, and 3A4. CYP1B1 had the highest 4-hydroxylation activity, followed by CYP1A2, 1A1, and 3A4. The 16alpha-hydroxylation reaction was catalyzed mainly by CYP1A2 and, to a similar, slightly lower extent, CYP3A4 and 1A1, with a lesser contribution by CYP1B1. The E(2) 2-, 4-, and 16alpha-hydroxylation activities of human liver microsomes were 1.3 +/- 0.3, 0.5 +/- 0.06, and 0.3 +/- 0.05 nmol metabolite/min/nmol P450, respectively. The contribution of CYP1A1 and 1B1 (mainly extrahepatic) to the E(2) hydroxylation reactions, relative to CYP1A2 and 3A4 (predominantly hepatic), may be relevant to understanding the process of hormonal carcinogenesis both in liver and in extrahepatic tissues.
Badawi
A F
AF
Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA. abadawi@unmc.edu
Cavalieri
E L
EL
Rogan
E G
EG
D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1 / Q000737:chemistry / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D004958:Estradiol / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008862:Microsomes, Liver / Q000737:chemistry / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D039181:Steroid 16-alpha-Hydroxylase
D007527:Isoenzymes; D011994:Recombinant Proteins; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C450259:CYP2C8 protein, human; C104464:CYP3A protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D039181:Steroid 16-alpha-Hydroxylase; C510163:CYP3A4 protein, human