Inhibition by retinoids of benzo(A)pyrene metabolism catalyzed by 3-methylcholanthrene-induced rat cytochrome P-450 1A1.
Benzo(a)pyrene, a well-known procarcinogen, is believed to be activated by microsomal cytochrome P-450 1A1 (CYP 1A1). We recently reported that rat CYP 1A1 induced by 3-methylcholanthrene (3-MC) catalyzed the conversion of retinal to retinoic acid. In this study, we investigated retinoid inhibition of the metabolism of benzo(a)pyrene and 7-ethoxyresorufin, another specific substrate of CYP 1A1, using liver microsomes prepared from control and 3-MC-pretreated rats as the enzyme source. In 3-MC-treated rats, retinal and retinol, but not retinoic acid, inhibited benzo(a)pyrene metabolism. The 50% inhibitory concentration (IC50) of retinal was about 11.5 micromol/L and the inhibition was competitive, with a Ki value of 5.8 micromol/L. Retinol is a more potent inhibitor than retinal. The IC50 was about 5 micromol/L and the inhibition was mixed, with a Ki value of 19.2 micromol/L and a Ki' value of 4.2 micromol/L. Almost the same results were obtained for the reaction of 7-ethoxyresorufin deethylation. In contrast, the metabolic activity of both benzo(a)pyrene and 7-ethoxyresorufin was much lower in untreated versus 3-MC-treated rats, and only weak inhibition by the retinoids was observed. The results suggest that retinoids inhibit the activation of benzo(a)pyrene and that the substrate specificity of cytochrome P-450 isozymes associated with retinoid metabolism should be taken into account when studying the anticarcinogenic action of retinoids.
Huang
D Y
DY
Department of Biochemistry, School of Medicine, Kagawa Medical University, Japan.
Ohnishi
T
T
Jiang
H
H
Furukawa
A
A
Ichikawa
Y
Y
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002273:Carcinogens / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D008297:Male; D008748:Methylcholanthrene; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012172:Retinaldehyde / Q000494:pharmacology; D012176:Retinoids / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology; D014801:Vitamin A / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D012176:Retinoids; D014801:Vitamin A; D001564:Benzo(a)pyrene; D008748:Methylcholanthrene; D014212:Tretinoin; D019363:Cytochrome P-450 CYP1A1; D012172:Retinaldehyde