Different susceptibility to peroxisome proliferator-induced hepatocarcinogenesis in rats with polymorphic glutathione transferase genes.
Although peroxisomal bifunctional enzyme (enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase; BE) is a positive marker for peroxisome proliferation, it is completely absent or expressed very weakly in rat hepatic preneoplastic and neoplastic lesions induced by peroxisome proliferators (PP). After administration of PP for 8-15 weeks, some rats exhibit BE-negative preneoplastic foci but other rats do not. In the present study, to investigate the involvement of glutathione S-transferase (GST) M1 gene polymorphism in interindividual differences in susceptibility to PP, we developed a method to determine the genotypes of rats. We then examined whether rats with one type encoding 198Asn-199Cys (NC-type) or another encoding 198Lys-199Ser (KS-type) exhibit differences in clofibrate (CF) susceptibility. After administration of 0.3% CF for 6 weeks or more, BE-negative foci were found immunohistochemically in KS/KS-type rats, but not in NC/NC-type rats. The number of BE-negative foci in KS/KS rats was 15.3 +/- 9.0 foci/cm2 of liver section after 6 weeks of CF administration, and the values did not alter thereafter. The mean areas of BE-negative foci in KS/KS rat livers increased during the period from 6 to 60 weeks. At weeks 30 and 60, almost all BE-negative foci exhibited a clear cell phenotype, a type of preneoplastic hepatic lesion. BE-negative foci were devoid of peroxisome proliferator-activated receptor alpha, whereas surrounding tissues were positive for the receptor. These results indicate that rats that are polymorphic for the GST M1 gene exhibit different susceptibilities to CF in vivo.
Kudo
Toshihiro
T
Second Department of Biochemistry, Hirosaki University School of Medicine, 5 Zaifu- cho, Hirosaki 036-8562, Japan.
Asano
Jumpei
J
Shimizu
Takeshi
T
Nanashima
Naoki
N
Fan
Yang
Y
Akita
Miki
M
Ookawa
Keizo
K
Hayakari
Makoto
M
Yokoyama
Yoshihito
Y
Suto
Kohji
K
Tsuchida
Shigeki
S
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000032:analysis / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002994:Clofibrate / Q000633:toxicity; D004746:Enoyl-CoA Hydratase / Q000032:analysis / Q000378:metabolism*; D005982:Glutathione Transferase / Q000235:genetics*; D007535:Isomerases / Q000032:analysis / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D009097:Multienzyme Complexes / Q000032:analysis / Q000378:metabolism; D047493:PPAR alpha / Q000032:analysis; D063994:Peroxisomal Bifunctional Enzyme; D020025:Peroxisome Proliferators / Q000633:toxicity*; D011110:Polymorphism, Genetic; D051381:Rats
D015094:3-Hydroxyacyl CoA Dehydrogenases; D002994:Clofibrate; D004746:Enoyl-CoA Hydratase; D005982:Glutathione Transferase; D007535:Isomerases; D009097:Multienzyme Complexes; D047493:PPAR alpha; D063994:Peroxisomal Bifunctional Enzyme; D020025:Peroxisome Proliferators