Genetic resistance to chemical hepatocarcinogenesis in the DRH rat strain.
The carcinogen-resistant inbred rat strain DRH established from closed-colony Donryu rats by use of selective brother-sister mating over 20 generations under continuous feeding of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) maintains a highly resistant phenotype without carcinogen exposure for many years. We reported that the clonal expansion of preneoplastic glutathione S-transferase-P(GST-P)-positive foci induced by 3'-Me-DAB was less extensive in the liver of DRH rats than in the liver of susceptible strains, such as Donryu and F344, although levels of DNA adducts were comparable among these rats. Comparative studies of the events after initiation indicate that DRH rats are constitutionally less prone to cellular damage caused by continuous administration of 3'-Me-DAB than are parental Donryu rats. Consequently, the reduced growth response of the liver during the promotion stage may contribute to the low susceptibility to development of liver tumors. Genetic analysis of (F344 x DRH)F2 rats identified two quantitative trait loci, Drh1 on chromosome 1 and Drh2 on chromosome 4, which provide resistance to the development of GST-P-positive preneoplastic foci induced by 3'-Me-DAB during the early stage of its administration. The resistance to progression to hepatocellular carcinoma is affected solely by Drh2. These observations indicate that at least two genetic loci are critically involved in the steps leading to chemical hepatocarcinogenesis. The DRH rat is a useful experimental model with which to study genetic susceptibility and resistance to chemically induced liver cancers.
Higashi
Ken
K
Department of Pathology and Biology of Diseases, Kyoto University Graduate School of Medicine, Yoshida-konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Denda
Ayumi
A
Higashi
Taneaki
T
Hiai
Hiroshi
H
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics; D018736:DNA Adducts; D006498:Hepatectomy; D022781:Hepatocytes / Q000502:physiology; D007113:Immunity, Innate / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics; D008749:Methyldimethylaminoazobenzene / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D051381:Rats; D011919:Rats, Inbred Strains
D018736:DNA Adducts; C035722:3'-methyl-4-diethylaminoazobenzene; D008749:Methyldimethylaminoazobenzene