Involvement of μ class glutathione S-transferase subunit M2 (rGST M2) levels in the initiation and promotion of hepatocellular carcinogenesis in old rats

Abstract Age-associated differences in the response of the initiation and promotion of hepatocellular carcinogenesis in the rat were analyzed. Male Wistar rats 5 and 18 months-old were used throughout. They underwent an experimental design of multistage model of hepatocarcinogenesis: hepatic cells were initiated with the complete carcinogen Aflatoxin B 1 (0.5 mg/Kg b.w.) and the promotion was performed through a combined treatment of proliferation (partial hepatectomy, 65%) and administration of the tumorigenic promoter phenobarbital (0.1% in drinking water for 21 days). After the treatment, rats were sacrificed and the following parameters were determined: activity and subunit composition of the glutathione S-transferase enzyme system, the number of liver preneoplastic foci and the proliferation cell index. The combined treatment (initiation+promotion) lowered the expression of the μ class GST (rGST M 1 , rGST M 2 ). The inhibition in rGST M 2 in old animals (which in basal conditions had already been lower) was significant. On the other hand, the treatment increased the α class GST (rGST A, rGST A 3 ). The number of preneoplastic foci was higher in old rats (number of foci/cm 2 : 6.9±0.3 vs 3.9±0.3 in young rats, p 2 deficiency coexisted with induced expression of α class, the livers would be resistant to some toxic insults, being selectively sensitive to potentially genotoxic substances for which M 2 is an essential detoxification pathway. The transition to a rGST M 2 -deficient phenotype during aging could induce higher responsiveness to genotoxic effects, and might favor the likelihood of further progression, indicating a higher suceptibility of aged animals to the development of carcinogenesis.