Evidence for cytochrome P-450NF, the nifedipine oxidase, being the principal enzyme involved in the bioactivation of aflatoxins in human liver.
In vitro studies with human liver indicate that the major catalyst involved in the bioactivation of the hepato-carcinogen aflatoxin B1 (AFB1) to its genotoxic 2,3-epoxide derivative is cytochrome P-450NF (P-450NF), a previously characterized protein that also catalyzes the oxidation of nifedipine and other dihydropyridines, quinidine, macrolide antibiotics, various steroids, and other compounds. Evidence was obtained using activation of AFB1 as monitored by umuC gene expression response in Salmonella typhimurium TA1535/pSK1002 and enzyme reconstitution, immunochemical inhibition, correlation of response with levels of P-450NF and nifedipine oxidase activity in different liver samples, stimulation of activity by 7,8-benzoflavone, and inhibition of activity by troleandomycin. Similar results were obtained when levels of 2,3-dihydro-2-(N7-guanyl)-3-hydroxyaflatoxin B1 formed in DNA were measured. P-450NF or a closely related protein also appears to be the major catalyst involved in the activation of aflatoxin G1 and sterigmatocystin, the latter compound being more genotoxic than AFB1 in these systems. Several drugs and conditions are known to influence the levels and activity of P-450NF in human liver, and the activity of the enzyme can be estimated by noninvasive assays. These findings provide a test system for the hypothesis that a specific human disease state (liver cancer) is linked to the level of oxidative metabolism in populations in which aflatoxin ingestion is high.
Shimada
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Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232.
Guengerich
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FP
D016604:Aflatoxin B1; D000348:Aflatoxins / Q000378:metabolism*; D000906:Antibodies / Q000276:immunology; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007120:Immunochemistry; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000276:immunology / Q000378:metabolism*; D009543:Nifedipine / Q000378:metabolism; D010084:Oxidation-Reduction; D013241:Sterigmatocystin / Q000378:metabolism; D014217:Troleandomycin / Q000494:pharmacology
D000348:Aflatoxins; D000906:Antibodies; D001571:Benzoflavones; D013241:Sterigmatocystin; C027955:aflatoxin G1; C011512:alpha-naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D014217:Troleandomycin; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D009543:Nifedipine