The effect of phenobarbital pretreatment on the metabolism, covalent binding, and cytotoxicity of aflatoxin B1in primary cultures of rat hepatocytes

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Abstract
The effect of phenobarbital (PB) pretreatment on the metabolism, covalent binding and cytotoxicity of [14C]aflatoxin B1 (AFB1) was studied in primary hepatocyte cultures. Hepatocytes from control and PB-pretreated rats were isolated from perfused liver biopsies and cultured in a chemically defined, hormone-supplemented medium. [14]AFB1, dissolved in medium, was added to cultures at 20-22 h. The metabolism of AFB1 to water-soluble products and its binding to trichloroacetic acid-precipitable macromolecules were assessed 0.5-24 h later. At 6 h, PB pretreatment reduced total binding to macromolecules by 31% and reduced binding to RNA and DNA by 61 and 66%, respectively. PB protected cultures from the cytotoxic effects of AFB1, as evidenced by a significantly reduced (P < 0.05) leakage of lactate dehydrogenase into the medium at 51 h. Elevated mixed-function oxidase and glutathione S-transferase activities, and higher levels of AFB1-glutathione conjugate were measured in cultures from rats pretreated with PB. The protective action of PB was due to the induction of hepatic glutathione S-transferases responsible for the detoxification of AFB1.

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