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Protection against toxic redox cycles between benzo(a)pyrene-3,6- quinone and its quinol by 3-methylcholanthrene-inducible formation of the quinol mono- and diglucuronide

W Lilienblum, BS Bock-Hennig and KW Bock

Cytotoxic effects of quinones are thought to be mediated by redox cycles between quinones and quinols whereby reactive oxygen species are generated. The role of glucuronidation in preventing these toxic redox cycles was investigated by using benzo(a)pyrene-3,6-quinone and isolated rat hepatocytes or Reuber hepatoma cells (H4IIE). Inhibition of quinol glucuronidation by salicylamide enhanced quinone-dependent oxygen uptake and cytotoxicity. Conjugation of benzo(a)pyrene-3,6- quinol was shown to proceed via the 6-monoglucuronide to the diglucuronide. Diglucuronide formation was low in hepatocytes from untreated controls and phenobarbital-treated rats. However, it was highly stimulated (26-fold) in hepatocytes from 3-methylcholanthrene- treated rats and was also high in Reuber hepatoma cells. Kinetic analysis with liver microsomes indicated that 3-methylcholanthrene- stimulated glucuronidation was due to an increased Vmax of UDP- glucuronosyltransferase which was enhanced 10- and 40-fold or mono- and diglucuronide formation, respectively. These findings suggest that the investigation of quinol glucuronidation (in particular the formation of benzo(a)pyrene-3,6-quinol diglucuronide) is a most useful probe for the 3-methylcholanthrene-inducible isoenzyme(s) of UDP- glucuronosyltransferase. Moreover, this isoenzyme may be particularly suited to protect against toxic redox cycles between benzo(a)pyrene quinones and quinols.

Volume 27, Issue 4, pp. 451-458, 04/01/1985
Copyright © 1985 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1985 by the American Society for Pharmacology and Experimental Therapeutics