Identification of cytochrome P450 isoforms involved in 1-hydroxylation of pyrene.
Urinary 1-hydroxypyrene (1-OHP) has been used as a biomarker for environmental polyaromatic hydrocarbon (PAH) exposure. However, it is known that there is an interindividual variability in metabolism of pyrene to 1-OHP depending on the activities of the metabolizing enzymes, especially cytochrome P450s (CYPs). In this study, we investigated the 1-hydroxylation of pyrene by 10 forms of cDNA-expressed human P450s in order to identify the principal isoforms of P450s that are involved in the major metabolic pathway of pyrene. The pyrene 1-hydroxylation activity was found to be the highest in CYP1A1 at both 0.5 and 50microM of pyrene, followed by CYP1B1 and 1A2, whereas other enzymes, including CYP2A6, 2C8, 2C9*1, 2C19, 2D6, 2E1, 3A4, and control microsomes, showed very low or undetectable rates of 1-hydroxylation. In conclusion, CYP1A1, 1B1, and 1A2 are major metabolizing enzymes in 1-hydroxylation of pyrene in vitro. This suggests that the individual difference of these enzymes must be included in epidemiological studies to evaluate PAH exposure using urinary 1-OHP.
Kim
Yong-Dae
YD
Department of Environmental Health, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
Todoroki
Hidekazu
H
Oyama
Tsunehiro
T
Isse
Toyohi
T
Matsumoto
Akiko
A
Yamaguchi
Tetsunosuke
T
Kim
Heon
H
Uchiyama
Iwao
I
Kawamoto
Toshihiro
T
D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011721:Pyrenes / Q000378:metabolism*
D018076:DNA, Complementary; D007527:Isoenzymes; D011721:Pyrenes; D003577:Cytochrome P-450 Enzyme System; C030984:pyrene; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; C033146:1-hydroxypyrene