Potentiation of the hepatic toxicity of carbon disulfide by chlordane

Abstract

Objectives:In this study, we investigated whether cytochrome P450s (CYPs) induced by a typical chlorinated hydrocarbon insecticide chlordane (CLD) potentiate hepatic toxicity of carbon disulfide (CS2).Materials and Methods:Male Sprague-Dawley rats were treated with CLD (25 mg/kg, intraperitoneally (i.p.)) daily for 4 days, and 24 h after the final injection the rats were treated with CS2 (380 mg/kg, i.p.) in corn oil; while controls received the vehicle alone. The rats were then sacrificed at 3, 6, and 24 h following the CS2 treatment.Results:It was found that at 3 h post-treatment, total hepatic glutathione (GSH) decreased modestly, but lipid peroxidation increased markedly, while all CLD-inducible CYPs (1A1, 2B1, 2E1, and 3A2) were inhibited by CS2 variably but significantly. On the other hand, samples taken at 24 h following the CS2 treatment showed a significant increase in relative liver weights, hepatic GSH and lipid peroxidation, microsomal reactive oxygen species (ROS), and serum alanine transaminase (ALT) level. Activity of the CYPs was also increased, but remained significantly depressed, especially that of CYP2B1. Livers removed at 3 and 6 h after CS2 treatment showed subtle to distinct apoptotic changes, while a severe lesion of hydropic degeneration of the centrilobular cells with apoptosis was microscopically distinguishable in samples taken at 24 h.Conclusions:These results suggest that the metabolism of CS2 by CLD-induced CYPs and the generation of lipid peroxides may have in concert contributed to the distinct hepatocellular damage.

Risk assessment of environmental mixture effects

“…This effect happens in both simultaneous and sequential exposures. 90 Another example of altered metabolism leading to potentiation is that of malathion, an extensively used pesticide that is oen contaminated during manufacture with an impurity called isomalathion. In combination, a mixture of the two has greater than expected cytotoxicity and genotoxicity 91 due to inhibition of carboxylesterases, another family of detoxication enzymes, by isomalathion.…”

The Increasing Prevalence in Intersex Variation from Toxicological Dysregulation in Fetal Reproductive Tissue Differentiation and Development by Endocrine-Disrupting Chemicals

“…H 2 S can inhibit cellular respiration creating oxidative stress and microsomal membrane changes, contributing to hepatic damage. 118,119 Carbon tetrachloride (CCl 4 ), a solvent and propellant, is more commonly known for its hepatotoxic and nephrotoxic capacity, but can also alter steroid hormone production pathways. Activation of CCL 4 causes cellular damage to the adrenal cortex, affecting cortisol function.…”

“…H 2 S can inhibit cellular respiration creating oxidative stress and microsomal membrane changes, contributing to hepatic damage. 118,119…”