Potentiation of the hepatic toxicity of carbon disulfide by chlordane.

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.

Effect of sympathectomy and demedullation on increased myenteric and dorsal vagal complex Fos-like immunoreactivity by cholecystokinin-8.

Chemical sympathectomy with daily, intraperitoneal (IP) injections of guanethidine sulfate to adult rats, attenuated myenteric, but not dorsal vagal complex (DVC) Fos-like immunoreactivity (Fos-LI) by cholecystokinin-8 (CCK). This technique destroys only 60-70% of the sympathetic neurons, and spares the hormonal source of catecholamines, the adrenal medulla. The goal of the current study is to evaluate the effect of complete sympathectomy or destroying 100% of the sympathetic neurons by injecting guanethidine to 1-day-old pups (40 mg/kg daily for 5 weeks), and surgically removing the adrenal medulla. In the DVC, demedullation and sympathectomy-demedullation increased Fos-LI by CCK in the area postrema and nucleus of the solitary tract, but sympathectomy-demedullation increased it only in the area postrema. In the myenteric plexus, sympathectomy increased this response in the duodenum, and demedullation increased it in the duodenum and jejunum. On the other hand, sympathectomy-demedullation attenuated myenteric Fos-LI in the jejunum. These results indicate that catecholamines may play an inhibitory role on the activation of the DVC neurons by CCK. In the myenteric neurons, however, catecholamines may have both inhibitory and excitatory roles depending on the level of the intestine e.g., duodenum vs. jejunum. This may also indicate that CCK activates the enteric neurons by different mechanisms or through different pathways.

Chemical sympathectomy attenuates myenteric but not dorsal vagal complex Fos-like immunoreactivity induced by cholecystokinin-8 in the rat.

Vagotomy and capsaicin treatment attenuate dorsal vagal complex (DVC) but not myenteric Fos-like immunoreactivity (Fos-LI) induced by cholecystokinin-8 (CCK-8). The goal of this experiment is to test the role of the sympathetic nervous system in the pathway by which CCK-8 increases myenteric Fos-LI. Adult male Sprague-Dawley rats were pretreated with guanethidine sulfate (40 mg/kg daily for 5 weeks) or vehicle intraperitoneally (IP), and injected with CCK-8 (40 microg/kg) or saline IP. Fos-LI was then quantified in the DVC and the myenteric neurons of the duodenum and jejunum using a diaminobenzidine reaction. Guanethidine pretreatment attenuated myenteric but not DVC Fos-LI induced by CCK-8. These findings demonstrate that sympathetic neurons play a role in mediating the myenteric Fos-LI response to CCK. They also suggest differential mediation of myenteric and DVC responses to CCK.

Effect of cytochrome P450 inducers on the metabolism and toxicity of thiram in rats.

Thiram is a dithiocarbamate compound widely used as an agricultural fungicide. This study examined the effect of cytochrome P450 (CYP) inducers on the metabolism and toxicity of thiram in rats. Rats were pretreated with 3-methyl cholathrene (3-MC), phenobarbital (PB), isoniazid (INH), or pregnenolone-16a-carbonitrile (PCN) as selective inducers of CYP 1A1, 2B1, 2E1 and 3A2, respectively. Thiram was administered ip to induced rats at 0.1 or 0.5 mmol/kg, and the animals were sacrificed 3 or 24 h later to assess P450 interaction and liver damage, respectively. No significant inhibition of 3-me-induced CYP1A1 was observed with either thiram dose at 3 or 24 h after treatment; similar results were noted for rats induced with PB or PCN. By contrast, when INH was the selective inducer of CYP2E1, there was significant inhibition by thiram 3 h and 24 h after treatment, suggesting that thiram was metabolized by the induced CYP2E1; there was a significant increase in ALT activity reflective of liver damage in the rats treated with thiram. The results suggest that CYP2EI induced by INH may be significantly involved in the metabolism of thiram, and the associated liver damage.