Lack of Hepatocarcinogenicity of Pentachlorophenol in Mmh/OGG1 Deficient Mice

Abstract

8-Oxoguanine (8-oxoG) has been paid attention due to its abundance and premutagenic property among a variety of oxidative DNA damages. The premutagenic 8-oxoG is known to cause its specific type of mutation after DNA replication, a GC to TA transversion, one of the mechanisms by which oxidative stress is involved in the aging process and the induction and progression of various diseases including carcinogenesis. As repair system against such premutagenicity of 8-oxoG, homolog of MutM and MutT in bacteria has been identified as Mmh/OGG1 and MH1 in mammals, respectively. The present study was investigated the repair system for 8-oxoG formation in hepatocarcinogenecity of pentachlorophenol (PCP), a wood preservative, using Mmh/OGG1 deficient mice. The deficient homo (KO), hetero and wild mice derived from C57BL strain were fed PCP at 600 ppm in diet for 26 weeks after initiation of single intraperitoneal injection of diethylnitrosoamine (DEN) at 100 mg/kg, and compared hepatic cancer development and hepatotoxicity to relevant controls. Although PCP treatment induced severe hepatotoxicity with inflammation, the treatment did not increase liver neoplastic lesion development with or without DEN initiation unexpectedly. Interestingly, the hepatocellualr proliferating activity in the homo mice given both of DEN and PCP treatment was significantly lower than that in the hetero and wild animals. In addition, increases of mRNA expression in major drug induced metabolic enzymes, cytochrome P450 1A2 and glutathione S-transferase were depressed in homo mice treated with PCP and DEN treatment. These results suggest that the hepatocarcinogenecity of PCP did not appear in Mmh/OGG1 gene deficient mice. Mechanisms of the negative results remain fully undetermined, but a genetic background in which C57BL mouse strain has resistant strain to hepatocarcinogenesis and any compensation pathway by other gene repair gene might be related. Lower potentials to drug-metabolism and cell proliferation activity in homo mice might accelerate the resistance.