Cytochrome P450-mediated metabolism and cytotoxicity of aflatoxin B(1) in bovine hepatocytes
| Autor: | R.F.M. Maas, Johanna Fink-Gremmels, M. E. M. Kuilman |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Aflatoxin
Aflatoxin B1 Cell Survival Metabolite Toxicology chemistry.chemical_compound fluids and secretions Cytochrome P-450 Enzyme System Cytochrome P-450 CYP1A1 Animals Cytochrome P-450 Enzyme Inhibitors MTT assay Bovine serum albumin Enzyme Inhibitors Carcinogen Biotransformation Benzoflavones biology Dose-Response Relationship Drug Cytochrome P450 General Medicine Glutathione bacterial infections and mycoses respiratory tract diseases Ketoconazole chemistry Biochemistry Liver Steroid Hydroxylases biology.protein Aflatoxin M1 Cattle Female |
| Zdroj: | Toxicology in vitro : an international journal published in association with BIBRA. 14(4) |
| ISSN: | 0887-2333 |
| Popis: | Aflatoxin B(1) (AFB(1)) biotransformation comprises cytochrome P450-mediated reactions resulting in hydroxylated and demethylated metabolites as well as AFB(1) epoxides. As the latter are highly nucleophilic, the species-specific rate of epoxidation and the ability for rapid conjugation to glutathione by glutathione S-transferase determines the individual susceptibility to AFB(1). Here we show the time- and dose-dependent rate of AFB(1)-metabolism in bovine hepatocytes. Aflatoxin M(1) (AFM(1)) is the most prominent metabolite formed within the first 2-8 hr of incubation, whereas AFB(1)-dhd is detectable in medium mainly after a prolonged incubation period. The delayed formation of AFB(1)-dhd corresponds to the cytotoxicity demonstrated by the MTT assay. alpha-Naphthoflavone and ketoconazole, inhibitors of CYP1A and CYP3A, respectively in humans, were used to evaluate the contribution of specific P450 isoenzymes in bovine biotransformation of AFB(1). Initial experiments confirmed that alpha-naphthoflavone and ketoconazole inhibited ethoxyresorufin O-deethylation and testosterone 6beta-hydroxylation also in bovine hepatocytes. Both inhibitors reduced AFM(1) and AFB(1)-dhd formation concentration dependently, suggesting that both enzyme groups contribute to the formation of these metabolites. However, the formation of AFM(1) was less inhibited by both compounds than the formation of AFB(1)-dhd. |
| Databáze: | OpenAIRE |
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