Formation of Reactive Metabolites of 14C-Naphthalene in Isolated Rat Hepatocytes and the Effect of Decreased Glucuronidation and Sulfation
Naphthalene is metabolized in the liver to its epoxide which either may be converted enzymatically to the glutathione conjugate or to the naphthalene dihydrodiol leading to quinones, or may rearrange non-enzymatically to the corresponding phenol (Jerina et al., 1970). Reactive metabolites are formed during biotransformation of naphthalene which bind irreversibly to proteins. Using microsomal fractions it has been shown that covalent binding of this aromatic hydrocarbon is mainly mediated via generation of naphthol and not by the primary epoxide (Hesse and Mezger, 1979). To examine whether secondary metabolism might also be important for the formation of reactive metabolites under conditions which more closely resemble those in vivo, we studied metabolism and binding of 14C-naphthalene in isolated rat hepatocytes. This system has been shown to be very suitable for toxicological studies as isolated hepatocytes exhibit neither the limitations of drug metabolism of subcellular fractions nor the complexity of the intact animal (Schwarz and Greim, 1981). Moreover, the system is easy to handle and allows selective modulation of drug metabolism. In the following, we describe the effect of decreased glucuronidation and sulfation on the steady state level of reactive metabolites of naphthalene.
KeywordsReactive Metabolite Water Soluble Metabolite Microsomal System Dihydrodiol Dehydrogenase Taurocholate Uptake
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