The role of human cytochrome P4503A4 in biotransformation of tissue-specific derivatives of 7H-dibenzo[c,g]carbazole

Journal Article · Thu Sep 15 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.06.027· OSTI ID:21587841

Mesarosova, Monika; Valovicova, Zuzana; Srancikova, Annamaria ^[1]; Krajcovicova, Zdenka ^[1]; Milcova, Alena ^[2]; Sokolova, Romana ^[3]; Schmuczerova, Jana; Topinka, Jan ^[2]; Gabelova, Alena ^[1]

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1. Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 833 91 Bratislava (Slovakia)
2. Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 20 Prague 4 (Czech Republic)
3. J. Heyrovsky Institute of Physical Chemistry, v.v.i., Academy of Sciences of the Czech Republic, Dolejskova 3, 18223 Prague (Czech Republic)

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 (30 {mu}M), revealed that this sarcomagenic carcinogen was also metabolized by hCYP3A4. Surprisingly, DBC increased the frequency of 6-thioguanine resistant (6-TG{sup r}) mutations only at the highest concentration (30 {mu}M), 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{sup r} mutants, while no changes in the nucleotide sequences were identified in 6-TG{sup 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. - Highlights: > DBC activation via CYP3A4 resulted in micronuclei, DNA adduct formation and mutations in V79MZh3A4 cells. > The CYP3A4-mediated DiMeDBC activation caused micronuclei followed by apoptosis in V79MZh3A4 cells. > The genotoxic effects produced by N-MeDBC in V79MZh3A4 cells were negligible. > The hCYP3A4 may play an important role in DBC and DiMeDBC metabolism. > The CYP3A4 might only have a marginal function in N-MeDBC metabolism.

• OSTI ID: 21587841
• Journal Information: Toxicology and Applied Pharmacology, Vol. 255, Issue 3; Other Information: DOI: 10.1016/j.taap.2011.06.027; PII: S0041-008X(11)00264-X; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
CARCINOGENS
DNA ADDUCTS
GENE MUTATIONS
HUMAN POPULATIONS
HYPOXANTHINE PHOSPHORIBOSYLTRANSFERASE
LIVER
METABOLISM
MUTANTS
NUCLEOTIDES
ADDUCTS
BODY
DIGESTIVE SYSTEM
ENZYMES
GLANDS
GLYCOSYL TRANSFERASES
MUTATIONS
ORGANIC COMPOUNDS
ORGANS
PENTOSYL TRANSFERASES
POPULATIONS
PROTEINS
TRANSFERASES