Effects of pretreatment with SKF-525A on triphenyltin metabolism and toxicity in mice

Abstract

The effects of cytochrome P-450 inhibition by α-phenyl-α-propylbenzeneacetic acid 2-[diethylamino]-ethyl ester hydrochloride (SKF-525A), which inhibits the activity of a number of cytochrome P-450s, on triphenyltin metabolism and toxicity in mice were studied. At 24 h after triphenyltin administration, the triphenyltin levels in the tissues of SKF-525A-pretreated mice were about three times of those in the tissues of SKF-525A-untreated mice and the ratio of metabolites to parent triphenyltin in the tissues of SKF-525A-pretreated mice was lower than those in the tissues of SKF-525A-untreated mice. These data indicate that the pretreatment of SKF-525A decelerated the triphenyltin metabolism and increased triphenyltin accumulation in the tissues of mice. Although triphenyltin did not affect plasma glucose levels of in the SKF-525A-untreated mice, the triphenyltin produced marked hyperglycemia in SKF-525A-pretreated mice. These results suggest that the inhibition of cytochrome P-450 system enzymes by SKF-525A affects the metabolism and toxicity of triphenyltin and has a key role in inducing the hyperglycemic action of triphenyltin, i.e. by increasing triphenyltin accumulation in the mice.

Introduction

Organotin compounds have become important commercial organometals. They have been used widely as agricultural pesticides, as antifouling paints for ship hulls and fishery firm nets and as stabilizers to lessen the effects of heat and light in polyvinyl chloride plastics (Blunden and Evans, 1990). Triorganotin derivatives, such as triphenyltin and tributyltin compounds, are highly embryotoxic, peripheral myopathy and genotoxic effects, etc. to mammals (Boyer, 1989, Kang et al., 1997, Chao et al., 1999) and some cases of human poisoning, hepatic injury, acute nephropathy or mucous membrane irritation, have been described (Colosio et al., 1991, Lin and Hsueh, 1993, Wax and Dockstader, 1995). In addition, the imposex associated with exposure to these compounds in mollusks as one of endocrine disruptive effects have recently become a matter of great concern (Matthiessen and Gibbs, 1998). A knowledge of the toxicological mechanism and metabolic fate of these compounds, therefore, is of considerable importance.

We have demonstrated previously that acute triphenyltin toxicosis induces hyperglycemia and hypertriglyceridemia in hamsters and rabbits, but these signs of intoxication were not found in rats and mice (Matsui et al., 1984). Similarly, species differences in the metabolic fate of triphenyltin exist for susceptibility between hamsters and rats. Hamsters were more susceptible than rats to the pancreatic accumulation of triphenyltin and high correlation was obtained between the tin concentrations in the pancreas and plasma glucose levels in triphenyltin-treated hamsters (Ohhira and Matsui, 1996). Furthermore, we also found that the diabetogenic actions of triphenyltin to hamsters were suppressed by pretreatment with phenobarbital (PB), which increased levels of cytochrome P-450 and accelerated metabolism of triphenyltin (Ohhira et al., 1999). These results suggest that the metabolic fate of triphenyltin may contribute to the toxicity of the chemical on hamsters. Hence, we investigated the effects of the inhibition of cytochrome P-450 system enzymes by α-phenyl-α-propylbenzeneacetic acid 2-[diethylamino]-ethyl ester hydrochloride (SKF-525A), an inhibitor of the PB-inducible forms (Lewis, 1996), on the metabolism and toxicity of the triphenyltin in mice, because mice are insusceptible to the hyperglycemic action by triphenyltin and are able to treat easily.