title: The role of human cytochrome P4503A4 in biotransformation of tissue-specific derivatives of 7H-dibenzo[c,g]carbazole.
abstract: The environmental pollutant 7H-dibenzo[c,g]carbazole (DBC) and its derivative, 5,9-dimethylDBC (DiMeDBC), produced significant and dose-dependent levels of micronuclei followed by a substantial increase in the frequency of apoptotic cells in the V79MZh3A4 cell line stably expressing the human cytochrome P450 (hCYP) 3A4. In contrast, neither micronuclei nor apoptosis were found in cells exposed to the sarcomagenic carcinogen, N-methylDBC (N-MeDBC). A slight but significant level of gene mutations and DNA adducts detected in V79MZh3A4 cells treated with N-MeDBC, only at the highest concentration (30μM), revealed that this sarcomagenic carcinogen was also metabolized by hCYP3A4. Surprisingly, DBC increased the frequency of 6-thioguanine resistant (6-TG(r)) mutations only at the highest concentration (30μM), while DiMeDBC failed to increase the frequency of these mutations. The resistance to 6-thioguanine is caused by the mutations in the hypoxanthine-guanine phosphoribosyltransferase (Hprt) gene. The molecular analysis of the coding region of Hprt gene showed a deletion of the entire exon 8 in DiMeDBC-induced 6-TG(r) mutants, while no changes in the nucleotide sequences were identified in 6-TG(r) mutants produced by DBC and N-MeDBC. Based on our results, we suggest that hCYP3A4 is involved in the metabolism of DBC and its tissue-specific derivatives. While hCYP3A4 probably plays an important role in biotransformation of the liver carcinogens, DBC and DiMeDBC, it might only have a marginal function in N-MeDBC metabolism.
authors.affiliation: Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, 833 91 Bratislava, Slovak Republic.
authors.forename: Monika
authors.initials: M
authors.lastname: Mesárošová
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Valovičová
authors.forename: Annamária
authors.initials: A
authors.lastname: Srančíková
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Krajčovičová
authors.forename: Alena
authors.initials: A
authors.lastname: Milcová
authors.forename: Romana
authors.initials: R
authors.lastname: Sokolová
authors.forename: Jana
authors.initials: J
authors.lastname: Schmuczerová
authors.forename: Jan
authors.initials: J
authors.lastname: Topinka
authors.forename: Alena
authors.initials: A
authors.lastname: Gábelová
mesh_terms: D000818:Animals; D001711:Biotransformation / Q000187:drug effects / Q000235:genetics; D002227:Carbazoles / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000502:physiology*; D006801:Humans
chemical_list: D002227:Carbazoles; C041150:N-methyl-7H-dibenzo(c,g)carbazole; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human