No direct hepatotoxic potential following a multiple-low dose paraquat exposure in rat as related to its bioaccumulation

Abstract

Paraquat (PQ) is a well-known toxic bipyridyl herbicide commonly used in agricultural countries. Pulmonary toxicity is the main cause of death but damage to other organs has also been reported. PQ is also classified as a "direct hepatotoxicant" following an acute high dose exposure. The evidence of multi-low dose toxicity of PQ was scarce. Therefore, the aim of this study was to examine the effect of multiple low doses of PQ on the liver function and xenobiotic-metabolizing enzyme activities including CYP1A1, 2E1, and 3A4, and to correlate the effects with its tissue accumulation. PQ, at the dose range 4.0-6.0 mg/kg day, was subcutaneously administered to male Wistar rats for seven consecutive days. The prominent feature of toxic response was lung toxicity. Interestingly, PQ-treatment caused a dose- and time-dependent reduction of plasma transaminase activity. Hypobilirubinemia and hypoalbuminemia were also observed without significant alteration in the liver morphology. Of all the xenobiotic-metabolizing enzymes being studied, only the activity of CYP1A1-related 7-ethoxyresorufin-O-deethylase was reduced following the highest dose of PQ administration. Plasma and tissue concentrations and accumulation of PQ analyzed by HPLC were dose-dependent showing much higher concentration (approximately 13 times) in the lung than that in the liver whereas it was undetectable in the plasma at the same time point. It can be concluded that multi-low dose PQ might affect certain synthetic function of the liver or activity of some hepatic xenobiotic-metabolizing enzymes. Minimal PQ accumulation in the liver is one of the explanations for the lack of cytotoxic hepatic injury in this study. Plasma PQ concentration may not be a good marker of exposure and toxicity after a prolonged exposure to PQ. © 2007 Elsevier Ireland Ltd. All rights reserved.