Pyrene-induced CYP1A2 and SULT1A1 may be regulated by CAR and not by AhR.
Aryl hydrocarbon receptor (AhR) plays important roles in the regulation and induction of xenobiotic-metabolizing enzymes including the cytochromes P450 1 family (CYP1) and UDP-glucuronosyltransferases 1A (UGT1As) by polycyclic aromatic hydrocarbons as well as chlorinated aromatic hydrocarbons. To determine whether pyrene-induced xenobiotic-metabolizing enzymes are regulated by AhR, male AhR (+/+) and (-/-) mice were used. Both genotyped mice were exposed to 0, 205, 300 or 410 mg/(kgday pyrene), once daily, for four consecutive days by gavage. Exposure to pyrene did not influence hepatic CYP1A1-mRNA in mice of both genotypes, whereas it induced hepatic CYP1A2 protein and mRNA expression and associated 7-ethoxyresorufin O-deethylase and pyrene 1-hydroxylation activities in both AhR (+/+) and (-/-) mice. Similar effects were also found with sulfotransferase 1A1 expression and the associated 1-hydroxypyrene sulfation activity. In contrast, pyrene exposure increased expression of the UGT1A1 and 1A6, and glucuronidation activities associated with 1-hydroxypyrene and 1-naphthol in the liver only in AhR (-/-) mice, although pyrene treatment dose-dependently decreased the latter activity. Pyrene exposure did not increase AhR-mRNA expression in AhR (+/+) mice. In contrast, pyrene-induced expression of the hepatic constitutive androstane receptor (CAR) and one of its target genes, CYP2B10, in both AhR (+/+) and (-/-) mice. These results strongly suggest that pyrene-induced CYP1A2 and SULT1A1 are regulated by CAR, not by AhR. However, the mechanisms of UGT1A1 and 1A6 induction by pyrene were not elucidated in this study.
Lee
Chul-Ho
CH
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
Ito
Yuki
Y
Yanagiba
Yukie
Y
Yamanoshita
Osamu
O
Kim
Heon
H
Zhang
Shu-Yun
SY
Kamijima
Michihiro
M
Gonzalez
Frank J
FJ
Nakajima
Tamie
T
D000818:Animals; D015239:Arylsulfotransferase / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D000090702:Constitutive Androstane Receptor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000633:toxicity; D005838:Genotype; D005965:Glucuronates / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006900:Hydroxylation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009284:Naphthols / Q000378:metabolism; D011721:Pyrenes / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D013379:Substrate Specificity; D014157:Transcription Factors / Q000502:physiology*
D000090702:Constitutive Androstane Receptor; D005456:Fluorescent Dyes; D005965:Glucuronates; D009284:Naphthols; D011721:Pyrenes; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C029350:1-naphthol; C030984:pyrene; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D014453:Glucuronosyltransferase; C107611:UDP-glucuronosyltransferase, UGT1A7; D015239:Arylsulfotransferase; C513291:Sult1a1 protein, mouse; C033146:1-hydroxypyrene