2-acetylaminofluorene : metabolism and effects on drug-metabolizing enzymes
Abstract: 2-Acetylaminofluorene has been found to have two different kinds of effects on drug-metabolizing enzymes in rat liver :1. Short-term treatment with this compound induces the level of microsomal epoxide hydrolase and cytochromes P-450b+e, c, d and PB/PCN-E, with a concominant increase in the metabolism of 2-acetylaminoflurene itself. Cytochromes P-450c and d have been found to be the most effective isozymes in both catalyzing ring- and N-hydroxylation of 2-acetylaminofluorene. All other isozymes tested have a lower activity, but also unique metabolitte patterns in the reconstituted system. 2-Aminofluorene, the deacetylated product, is the metabolite responsible for the induction of cytochrome P-450c, while the parent compound and other metabolites seem to be more effective in inducing other isozymes of cytochrome P-450 and microsomal epoxide hydrolase. Also increased to a small extent are cytosolic glutathione transferase and DT-diaphorase activities.2. Long-term dietary exposure to 2-acetylaminofluorene, resulting in hepatocyte nodules, gives a different picture, i.e., decreases in the total content of cytochrome P-450 and and a number of cytochrome P-450-dependent activities, including ring and N-hydroxylation of 2-acetylaminofluorene itself.The activities of microsomal epoxide hydrolase, cytosolic glutathione transferase, UDP-glucuronyl transferase and cytosolic DT-diaphorase are dramatically increased in nodules.
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