title: Oxidative DNA damage and reporter gene mutation in the livers of gpt delta rats given non-genotoxic hepatocarcinogens with cytochrome P450-inducible potency.
abstract: Previous reports have proposed that reactive oxygen species resulting from induction of cytochrome P450 (CYP) isozymes might be involved in the modes of action of hepatocarcinogens with CYP-inducible potency. In the present study, we investigated 8-hydroxydeoxyguanosine (8-OHdG) levels, in vivo mutagenicity and glutathione S-transferase placental form (GST-P)-positive foci in the livers of gpt delta rats treated with piperonyl butoxide (PBO) or phenobarbital (PhB) for 4 and 13 weeks. Significant elevations in Cyp 1A1 and Cyp 1A2 mRNA levels after PBO treatment, and in Cyp 2B1 mRNA levels after PBO or PhB treatment, appeared together with remarkable hepatomegaly through the experimental period. Time-dependent and statistically significant increases in 8-OHdG levels were observed in the PBO treatment group along with significant increases in proliferating cell nuclear antigen (PCNA)-positive hepatocytes at 4 weeks, while no increase in 8-OHdG levels was found in PhB-treated rats. No changes in mutant frequencies of gpt and red/gam (Spi(-)) genes in liver DNA from PBO- or PhB-treated rats were observed at 4 or 13 weeks. A 13-week exposure to either PBO or PhB did not affect the number and area of GST-P-positive hepatocytes. CYP 1A1 and 1A2 induction may be responsible for elevated levels of 8-OHdG in PBO-treated rats. However, neither GC:TA transversions nor deletion mutations, typically regarded as 8-OHdG-related mutations, were observed in any of the treated rats. We conclude that reactive oxygen species, possibly produced through CYP catalytic pathways, likely induced genomic DNA damage but did not give rise to permanent gene mutation.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Kamiyoga, Setagaya-ku, Tokyo, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Tasaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Umemura
authors.forename: Yuta
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hibi
authors.forename: Tomoki
authors.initials: T
authors.lastname: Inoue
authors.forename: Toshiya
authors.initials: T
authors.lastname: Okamura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Soichi
authors.initials: S
authors.lastname: Maruyama
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishikawa
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D029968:Escherichia coli Proteins / Q000235:genetics*; D017930:Genes, Reporter / Q000235:genetics*; D005982:Glutathione Transferase / Q000096:biosynthesis; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics; D010430:Pentosyltransferases / Q000235:genetics*; D010634:Phenobarbital / Q000633:toxicity; D010882:Piperonyl Butoxide / Q000633:toxicity; D000091402:Prohibitins; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002273:Carcinogens; D029968:Escherichia coli Proteins; C000717332:Phb protein, rat; D000091402:Prohibitins; D018809:Proliferating Cell Nuclear Antigen; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003577:Cytochrome P-450 Enzyme System; D010430:Pentosyltransferases; C071962:Gpt protein, E coli; D005982:Glutathione Transferase; D003849:Deoxyguanosine; D010882:Piperonyl Butoxide; D010634:Phenobarbital