Abstract
Benzo( a)pyrene (BP) quinones and 3-OH-BP are the metabolites preferentially converted to glucuronyl conjugates when BP is metabolized by microsomes from 3-methyl-cholanthrene (MC)-treated rats in the presence of NADPH, O 2, and UDP-glucuronic acid (UDPGA). No glucuronyl conjugates of [ 14C]BP-3,6-quinone are formed in the absence of NAD(P)H, indicating that BP quinones must be reduced prior to glucuronylation. The observations that NADH can replace NADPH in BP-3,6-quinone glucuronylation and that these reactions are equally sensitive to dicoumarol, a potent inhibitor of DT-diaphorase, suggest that the reduction of BP-3,6-quinone preceding glucuronylation is catalyzed by DT-diaphorase. Furthermore, trypsin-treated microsomes, which have unchanged DT-diaphorase activity but less than 5% of original NADPH-cytochrome c reductase activity, exhibit unaltered capacity for the conversion of BP-3,6-quinone to glucuronyl conjugates. Analysis of ethyl acetate extracts from incubations with [ 14C]BP-3,6-quinone by high pressure liquid chromatography reveals that BP-3,6-quinone can be further metabolized by MC-induced microsomes to more polar but still water-insoluble products. These metabolites are not formed in the absence of NADPH or in trypsin-treated microsomes, which have no detectable aryl hydrocarbon monooxygenase (AHM) activity, indicating that the further metabolism of BP-3,6-quinone proceeds through the AHM system. The rate of this reaction and of glucuronylation of BP-3,6-quinone is very similar. The glucuronylation of 3-OH-BP by MC-induced microsomes is also inhibited by dicoumarol, whereas that of p-nitrophenol, methylumbelliferone or phenolphtalein is not. Trypsin treatment of microsomes strongly enhances 3-OH-BP glucuronylation. Evidence is presented suggesting that the dicoumarol effect is probably not due to an inhibition of UDP-glucuronosyltransferase, and the possibility is considered that a DT-diaphorase dependent rearrangement of 3-OH-BP prior to glucuronylation may be responsible for the observed dicoumarol sensitivity.
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