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

摘要

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 B1 (0.5mg/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 mu class GST (rGST M1, rGST M2). The inhibition in rGST M2 in old animals (which in basal conditions had already been lower) was significant. On the other hand, the treatment increased the alpha class GST (rGST A, rGST A3). 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< 0.05). The proliferation cell index did not show age-related differences. Because rGST M2 deficiency coexisted with induced expression of alpha class, the livers would be resistant to some toxic insults, being selectively sensitive to potentially genotoxic substances for which M2 is an essential detoxification pathway. The transition to a rGST M2-deficient phenotype during aging could induce higher responsiveness to genotoxic effects, and might favor the likelihood of further progression, indicating a higher susceptibility of aged animals to the development of carcinogenesis.