TISSUE-SPECIFIC DIFFERENCES IN ADDUCT FORMATION BY HEPATOCARCINOGENICAND SARCOMATOGENIC DERIVATIVES OF 7H-DIBENZO[C,G]CARBAZOLE IN MOUSE PARENCHYMAL AND NONPARENCHYMOL LIVER-CELLS

Parenchymal (PC)and nonparenchymal(NPC) liver cells have different tis sue-specific, procarcinogen activation enzymes. NPC appear to be prote cted against the mutagenic effects of lipotropic bulky adducts induced by carcinogens by a unknown mechanism. Most studies of activation hav e been conducted with whole liver. The purpose of this stud was to dif ferentiate adduct formation in mouse PC and in NPC, isolated after in vivo administration of 7H-dibenzo[c,g]carbazole (DEC), the most effici ent liver carcinogen in mice, which also has potent sarcomagenic and e pitheliomagenic activities. The very sensitive P-32-postlabeling metho d was used to detect adducts. Two tissue-specific DEC derivatives, 6-m ethoxy-DBC (6MeODBC), which is exclusively sarcomagenic, and 5,9-dimet hyl-DBC (DiMeDBC), which is exclusively hepatocarcinogenic, were analy zed in parallel. Both PC and NPC generated the ultimate metabolites of DEC, but NPC were substantially less efficient. Clear-cut tissue-spec ific differences in adduct formation were established: the sarcomageni c 6MeODBC gave rise only to NPC-DNA adducts, and the hepatocarcinogeni c DiMeDBC only to PC-DNA adducts. The chromatograms of the adducts wer e compared with those of mouse embryonic cells in culture and mouse ep idermal cells. The results ore discussed in connection with animal exp eriments with DEC, 6MeODBC, and dimethylbenzanthracene and with publis hed data on PC and NPC activating enzymes. (C) 1997 Wiley-Liss, Inc.