Low dose DDT inhibition of hepatocarcinogenesis initiated by diethylnitrosamine in male rats: possible mechanisms.
Previously we reported a tendency for reduction of the development of glutathione-S-transferase placental form (GST-P) positive foci, recognized as preneoplastic changes in rat liver, by a low dose of 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), which belongs to the same group of hepatic cytochrome P-450 inducers as phenobarbital and is itself a non-genotoxic hepatocarcinogen. In order to clarify the biological significance of this phenomenon, we investigated the reproducibility and changes in other parameters using an initiation-promotion model in which male F344 rats were treated with DDT at doses of 0, 0.005, 0.5, 500 ppm in the diet for 11 or 43 weeks after initiation of hepatocarcinogenesis with N-diethylnitrosamine (DEN). When 500 ppm DDT was applied, the formation of GST-P positive foci and tumor were markedly elevated. In contrast, induction of GST-P positive foci and liver tumors tended to be inhibited at a dose of 0.005 ppm, correlating with protein levels of cytochrome P450 2B1 and 3A2 (CYP2B1 and 3A2) and generation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. mRNA levels for 8-oxoguanine glycosylase 1 (OGG1), an 8-OHdG repair enzyme, connexin 32 (Cx32), a major component of Gap junctions, and hepatic nuclear factor 1alpha (HNF-1alpha), a Cx32 regulator, were inversely correlated with GST-P positive foci and tumor formation. These results indicate that low dose DDT may indeed exhibit inhibitory effects on chemically initiated-rat hepatocarcinogenicity, in contrast to the promotion observed with high doses, and that this is related to changes in metabolizing enzymes, cell communication, and DNA damage and its repair.
Kushida
Masahiko
M
Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan; Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 1-98, 3-chome, Kasugade-Naka, Konohana-ku, Osaka 554-8558, Japan.
Sukata
Tokuo
T
Uwagawa
Satoshi
S
Ozaki
Keisuke
K
Kinoshita
Anna
A
Wanibuchi
Hideki
H
Morimura
Keiichirou
K
Okuno
Yasuyoshi
Y
Fukushima
Shoji
S
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017630:Connexins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D003634:DDT / Q000008:administration & dosage / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D045647:DNA Glycosylases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000187:drug effects; D003849:Deoxyguanosine / Q000037:antagonists & inhibitors; D004052:Diethylnitrosamine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015870:Gene Expression; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D007120:Immunochemistry / Q000379:methods; D007274:Injections, Intraperitoneal; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D003577:Cytochrome P-450 Enzyme System; D003634:DDT; D045647:DNA Glycosylases; D004277:DNA, Single-Stranded; D003849:Deoxyguanosine; D004052:Diethylnitrosamine; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D051538:Hepatocyte Nuclear Factor 1-alpha; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D000097002:Gap Junction beta-1 Protein; C496558:Gstp1 protein, rat; C483741:OGG1 protein, rat