Promotor effect of S-metolachlor generics with different hepatotoxicity in liver carcinogenesis in rats

Abstract

Metolachlor and currently its biological active isomer S–metolachlor is one of the most widely used herbicides in the world. Chronic experiments in rats have found hepatocarcinogenic effect of metolachlor, and epidemiological studies have found positive relationship between enzyme exposure to metolachlor and prevalence of liver cancer. Possibility of the influence of harmful impurities contained in technical products on the detected effects is emphasized. Objective is to study promotor effect of S–metolachlor generics with different hepatotoxicity in carcinogenesis of liver in rats induced by nitrosodiethylamine (NDEA) and analyse possibility of its realisation in human. Materials and Methods. Experiments were performed in male Wistar Han rats on hepatocarcinogenesis model “NDEA — hepatectomy”. Two specimens of S–metolachlor generics were studied; and their ratio of S/R enantiomers was 87/13 % with different hepatotoxicity. Substances were administered intragastrically in the doses of 1.5,15 and 150 mg/kg body weight for 8 weeks. Animals of the negative control group received water, and positive control — phenobarbital. Promotor effect was evaluated by the standardised parameters of the total area and number of hepatocyte foci expressing γ-glutamyl transpeptidase (GTP). Results. No clinical signs of the toxic action of S–metolachlor on the rat body induced to carcinogenesis by NDEA were found. Increase in the number and total area of γ-GTP positive foci in the liver of animals on tumorogenic dose of both specimens of S–metolachlor as well as phenobarbital was found. Mean area of focus in the liver of rats on more toxic specimen was lower. The threshold of promotor action of S–metolachlor on hepatocarcinogenesis has been established at the level of γ 15 mg/kg body weight. Analysis of literature data on the mechanism of hepatotoxic action of metolachlor allowed to make a conclusion aboutphenobarbital-like mechanism of promotor action that is realised through constitutive androstane receptor (CAR). This mechanism is species-specific for rodents; therefore, the results of epidemiological studies on the possibility of liver cancer in human cannot be confirmed experimentally. Conclusion. Tumorogenic dose of S–metolachlor generics with different degree of hepatotoxicity shows promotor effect in NDEA induced carcinogenesis in rat liver. Hepatotoxicity of S–metolachlor inhibits growth of γ-GTP positive foci. The threshold of hepatocarcinogenesis promotion has been established at the level of γ 15 mg/kg body weight. The mechanism of the observed effect is not relevant for human. Key Words: S–metolachlor, hepatocarcinogenesis initiated by nitrosodiethylamine, Wistar Han rats, γ-glutamyltranspeptidase.