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Carcinogenesis, Vol. 23, No. 1, 189-196, January 2002
© 2002 Oxford University Press

CARCINOGENESIS

Resistance of DRH strain rats to chemical carcinogenesis of liver: genetic analysis of later progression stage

Ying Yan, Zhao-Zhu Zeng1, Shin Higashi1, Ayumi Denda2, Yoichi Konishi2, Shunzo Onishi3, Hikaru Ueno, Ken Higashi1 and Hiroshi Hiai1,4

Department of Biochemistry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-Ku, Kitakyushu 807-8555, Japan,
1 Department of Pathology and Biology of Diseases, Kyoto University Graduate School of Medicine, Yoshida-Konoe-Cho, Sakyo-Ku, Kyoto 606-8501, Japan,
2 Department of Oncology, Cancer Institute, Nara Medical University, Kashihara, Nara 634-8521, Japan and
3 Division of Pathology, Laboratory Center, Tane General Hospital, Nishi-Ku, Osaka 550-0024, Japan

The inbred DRH rats are highly resistant to the induction of hepatocellular carcinoma (HCC) by feeding of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB). Previously, we found that two quantitative trait loci (QTLs), Drh1 and Drh2, significantly reduced the number, size and area of glutathione S-transferase-placental form (GST-P)-positive foci and GST-P mRNA levels in (F344xDRH)F2 rat livers induced by feeding 3'-Me-DAB for 8 weeks. It is unclear, however, whether these QTLs affecting pre-neoplastic lesions are also the determinants of the later stage hepatocarcinogenesis, and whether there are any additional QTLs affecting hepatocarcinogenesis in the progression stage. To answer these questions, we analyzed QTL parameters for liver tumors in 99 (F344xDRH)F2 rats induced by feeding 3'-Me-DAB for 20 weeks. The QTL parameters examined were GST-P mRNA, ornithine decarboxylase activity, and the number and total area of HCC/nodules macroscopically detectable on the liver surface. In composite interval mapping, we observed two major QTL peaks overlapping on the map positions of Drh1 on rat chromosome 1 (RNO1) and Drh2 on RNO4, respectively. The newly mapped QTL on RNO1 affected the GST-P mRNA level at 20 weeks of 3'-Me-DAB feeding, but did not affect the number and size of tumors. The primary effect of Drh1 is, therefore, to inhibit GST-P induction and to prevent enzyme altered foci (EAF) formation. On the other hand, the QTLs on RNO4, co-mapped to Drh2, affected all parameters of liver tumors examined except for the level of GST-P mRNA. The latter QTLs influenced not only the induction of GST-P and formation of EAF but also the progression of tumors in the later stage of hepatocarcinogenesis. The GST-P induction is differentially controlled by stages of hepatocarcinogenesis and the DRH resistance to carcinogenesis is principally attributed to the QTLs on RNO4 out of two resistance QTLs identified in the pre-neoplastic stage.


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