In vitro cytochrome P450 monooxygenase and prostaglandin H-synthase mediated aflatoxin B1 biotransformation in guinea pig tissues: effects of beta-naphthoflavone treatment.
In the present study, we examined the effects of treating guinea pigs with beta-naphthoflavone (BNF) on aflatoxin B1 (AFB1) metabolism by microsomal cytochrome P450 monooxygenase (P450) and prostaglandin H synthase (PHS) in liver, lung and kidney tissues. After BNF treatment, microsomal 7-ethoxyresorufin O-deethylase activity was induced 13-, 25- and 11-fold in lung, kidney and liver, respectively, confirming that the BNF treatment protocol was effective at inducing monooxygenase activity. Treatment of guinea pigs with BNF did not change [3H]AFB1-DNA binding catalyzed by microsomal PHS or P450 in lung, kidney or liver. In contrast, AFM1 formation by P450 was significantly increased in microsomes from all three organs. The data indicate that BNF-inducible P450 isozymes of the P4501A class are responsible for the biotransformation of AFB1 to non-toxic metabolites. Guinea pig kidney microsomes could also catalyze NADPH-dependent formation of aflatoxicol (AFL), a metabolite usually produced by a cytosolic steroid dehydrogenase. Renal microsomal AFL formation was not altered by prior BNF treatment. The results in the present study suggest that BNF may alter the bioactivation of AFB1 in guinea pig tissues by inducing P450 activity, leading to the formation of less reactive metabolite.
Liu
L
L
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Nakatsu
K
K
Massey
T E
TE
D016604:Aflatoxin B1 / Q000378:metabolism / Q000493:pharmacokinetics*; D000348:Aflatoxins / Q000378:metabolism; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology*; D001711:Biotransformation; D001835:Body Weight / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts; D006168:Guinea Pigs; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D014316:Tritium; D019324:beta-Naphthoflavone
D000348:Aflatoxins; D001571:Benzoflavones; D018736:DNA Adducts; C072611:aflatoxin B1-DNA adduct; D014316:Tritium; C012170:aflatoxicol; D019324:beta-Naphthoflavone; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D010088:Oxidoreductases; D010105:Oxygenases; D019363:Cytochrome P-450 CYP1A1; D011451:Prostaglandin-Endoperoxide Synthases