title: Metabolism of benzene in rat hepatocytes. Influence of inducers on phenol glucuronidation.
abstract: Alterations of benzene metabolism in liver markedly influence benzene toxicity at extrahepatic target tissues. Therefore, generation of 11 phase I and II metabolites of benzene (including phenol, hydroquinone, catechol, benzene-1,2-dihydrodiol, their sulfates and glucuronides, and phenylglutathione) was compared in hepatocytes from 3-methylcholanthrene (MC)- or phenobarbital-treated rats and from untreated controls. At 0.1 mM benzene, total metabolism appeared to be unchanged by treatment with inducers. Phenylsulfate (35%), phenylglucuronide (15%), and phenylglutathione (12%) represented the major metabolites in hepatocytes from untreated controls. With hepatocytes from MC-treated rats, a pronounced shift from phenylsulfate to phenylglucuronide (increase to 34%) was observed, while the formation of unconjugated phenol, hydroquinone, and catechol was decreased (from 16 to 10%). A similar shift from sulfation to glucuronidation was seen in similar studies with phenol. Lineweaver-Burk analysis of microsomal phenol UDP-glucuronosyltransferase activity suggested that MC-treatment induced a high affinity isozyme (KM = 0.14 mM), in addition to the low affinity isozyme (KM = 3.1 mM) present in liver microsomes from untreated and phenobarbital-treated rats. It is concluded that induction by MC of a high affinity hepatic phenol UDP-glucuronosyltransferase effectively shifts benzene metabolism toward formation of less toxic metabolites. This shift may reduce toxic risks at extrahepatic target tissues.
authors.affiliation: Institute of Toxicology, University of Tübingen, FRG.
authors.forename: D
authors.initials: D
authors.lastname: Schrenk
authors.forename: K W
authors.initials: KW
authors.lastname: Bock
mesh_terms: D000818:Animals; D001554:Benzene / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005965:Glucuronates / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D010636:Phenols / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet; D013431:Sulfates / Q000378:metabolism
chemical_list: D005965:Glucuronates; D010636:Phenols; D013431:Sulfates; D008748:Methylcholanthrene; D014453:Glucuronosyltransferase; D001554:Benzene; D010634:Phenobarbital