Biochemical effects of chloral hydrate on male rats following 7-day drinking water exposure

Abstract

The biochemical and toxicological effects of chloral hydrate were investigated. Four groups (n = 7 per group) of male Sprague‐Dawley rats (161–170 g) were administered chloral hydrate in drinking water at concentrations of 20, 200 or 2000 ppm for 7 days. The control group received phosphate‐buffered water only. There were no treatment‐related changes in the body weight gains, relative weights of major organs or haematological parameters. Trichloroacetic acid was significantly (P < 0.05) elevated in the serum of high‐dose animals (7.75 ± 5.14 mg dl−1, mean ± SD). In the high‐dose animals there was a 36% increase in protein level in the liver homogenates but not in the corresponding 9000 g supernatants. Concurrently, there was a threefold increase in the activity of the hepatic peroxisomal enzyme palmitoyl CoA oxidase (PCO). A prominent change was the dose‐related suppression in hepatic aldehyde dehydrogenase (ALDH) activity observed in all treatment groups, with the decrease ranging from 15% at 20 ppm to 68% at 2000 ppm. There were no significant decreases in the activity of hepatic enzymes ethoxyresorufin O‐deethylase (EROD), benzyloxyresorufin O‐dealkylase (BROD) and UDP‐glucuronosyl‐transferase (UDPGT). In the high‐dose group there was a 30% increase in hepatic glutathione‐S transferase (GST) activity, accompanied by a 13% increase in glutathione (GSH). Significant effects on lipids were observed in the liver of the high‐dose animals, with a 15% decrease in hepatic cholesterol and triglyceride levels. There were no treatment‐related changes in serum chemistry parameters, including cholesterol and triglyceride levels. Although in vitro assays showed chloral hydrate to be an inhibitor of serum pseudocholinesterase activity, with a 50% inhibition concentration (ic50( of ∼ 0.7 mM at 5 mM butyrylthiocholine, no decrease in serum pseudocholinesterase activity was found in the treated animals. It was concluded that the liver is the target organ for chloral hydrate, with suppression of ALDH as the most sensitive endpoint followed by alteration in the GSH level and GST activity. Changes observed in the high‐dose animals, such as increased peroxisomal PCO activity in the liver and perturbation of lipid homeostasis in the liver and blood, were likely to be associated with trichloracetic acid, the major metabolite of chloral hydrate. Copyright © 2000 John Wiley & Sons, Ltd.

Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application

“…Chloral is a competitive substrate of ALDH with a slow k cat and IC 50 values ranging from 1 to 10 M (Poon et al, 2002). In vivo, its metabolites include trichloroacetic acid, proving that it functions as a substrate (Poon et al, 2000) there by being capable of inhibiting the metabolism of other aldehydic substrates of ALDHs. The mechanism by which it inhibits ALDH is thought to involve reversible thiohemiacetal formation with Cys302 in the active site.…”

Evaluation of neurotoxic and immunotoxic effects of trichloroacetic acid on rats

“…The effects of trichloroacetic acid (TCA) in various vertebrates have already been investigated in several studies (Acharya et al, 1995;Bryant, 1992;Mather et al, 1990;Poon et al, 2000;Poon et al, 2002), but results concerning vertebrates are both very limited. In the literature, it is reported that TCA causes changes in biochemical parameters on rats following drinking water exposure (Celik and Temur, 2009;Poon et al, 2000). Poon et al (2002) investigated that TCA treatments caused different effects on gross and microscopic examinations, serum chemistry, haematology, biochemical analysis and neurogenic amine at the end of the TCA treatment.…”