Evolution of activation-detoxification enzyme patterns during precarcinogenesis in synergism: 3-methylcholanthrene and dimethylnitrosamine.

Abstract

The effects of 3-methylcholanthrene (3MC) and dimethylnitrosamine (DMN), administered singly or in combination at chronic carcinogenic doses, on the evolution of activity patterns of enzymes involved in the metabolism of DMN and polycyclic hydrocarbons were studied in the liver and lung of Sprague-Dawley rats and Swiss mice. In the pulmonary tissues of rats, during the early stage of administration (7 weeks), there was substantial increase of epoxide hydrase and glutathione S-epoxide transferase activity; from then on these detoxifying enzyme activities rapidly decreased toward 25 weeks, and this decreasing trend coincided with a substantial surge of aryl hydrocarbon hydroxylase (AHH) activity at 15 weeks; 65%, 95%, and 50% increase with 3MC, DMN, and DMN+3MC, respectively. The activity of DMN-demethylase was slightly increased following treatment with DMN or DMN+3MC for 15 weeks. On the other hand, decrease of DMN-demethylase activity in the liver of rats throughout most of the experimental period was apparent and, after an initial small increase at 7 weeks, there was a trend of decreasing AHH activity from 7 toward 25 weeks with DMN+3MC; the 7-week increase in AHH was moreover compensated by the large increases in the activity of the three detoxifying enzymes, epoxide hydrase, glutathione S-epoxide transferase, and UDP-glucuronyl transferase at the same period. The data suggest that the previously observed pulmonary syncarcinogenesis between 3MC and DMN in rats (Hoch-Ligeti et al. 1968) is probably due to increase of reactive metabolites of both 3MC and DMN. In the mouse liver, a combination of initial increase of epoxide hydrase and UDP-glucuronyl transferase activity at 5 weeks, together with decrease of AHH activity at 10 weeks, suggests a decrease of activated hydrocarbon metabolites available for binding to macromolecules. While AHH activity showed a strongly decreasing trend in the mouse lung, increases of 21%, 30%, and 113% in DMN-demethylase activity were observed after the mice were given 3MC, DMN, or DMN+3MC, respectively, for 10 weeks. The pulmonary syncarcinogenic effect of 3MC and DMN in mice (Cardesa et al. 1973; Argus et al. 1982) appears to be due primarily to increase of reactive metabolite(s) of DMN. The data are consistent with previous observations (Arcos et al. 1978) that activated metabolites originating from liver are unlikely to be contributors in DMN+3MC pulmonary syncarcinogenesis.