One-Day Dietary Restriction Changes Hepatic Metabolism and Potentiates the Hepatotoxicity of Carbon Tetrachloride and Chloroform in Rats

Abstract

Although dietary restriction (DR) is common in modern society, research about hepatic metabolism and the hepatotoxicity induced by DR has been conducted less intensively than that induced by fasting. In the present study, we fed male Wistar rats at five levels of food intake for one day, including conventional feeding (60 kcal), three of DR (45, 30, and 15 kcal), and fasting (0 kcal), and observed the metabolic changes of hepatic cytochrome P450 2E1(CYP2E1) and the hepatotoxicity of chloroform (CHCl 3 ) and carbon tetrachloride (CCl 4 ). The CYP2E1 content was significantly increased in 15 kcalfood and fasting groups. The hepatic glutathione (GSH) content, which protects the liver from hepatotoxic agents, was depleted in 15 kcal-food and fasting groups. After the challenge by CHCl 3 and CCl 4 , the activities of aspartate aminotransferase and alanine aminotransferase, marker enzymes for liver damage, were elevated remarkably at all food groups. Moreover, their activities increased significantly in DR groups, in comparison to the corresponding 60 kcal-food group. After the challenge, the hepatic GSH content was also depleted significantly in 15 kcal-food and fasting groups. CHCl 3 was cleared by hepatic metabolism about 8-10 times faster than that of CCl 4 . Similarly, the areas under the blood concentration-time curve of CCl 4 was as much as twice that of the corresponding CHCl 3 . In conclusion, when food was restricted to less than half of conventional amount, hepatic metabolism was affected and the hepatotoxicity induced by CCl 4 or CHCl 3 was augmented by, at least in part, CYP2E1 induction and GSH depletion. dietary restriction; hepatotoxicity; hepatic cytochrome P450 2E1; chloroform; carbon tetrachloride

Chloroform-induced oxidative stress in rat liver: Implication of metallothionein

“…The most useful indicator of hepatic injury is primarily serum ALT-and secondarily AST-activity (Qin et al, 2007). The lowest CHCl 3 treatment dose used in this study (150 mg/kg), in accord with the findings of Gemma et al (1996), did not cause any increase in transaminases activities, except the relatively small effect observed with ALT when CHCl 3 was administered twice.…”

“…Serum alanine transaminase (ALT) and aspartate transaminase (AST) activities were determined as indices of liver injury (Qin et al, 2007). ALT and AST were estimated according to the methods described by Murray (1984 a, b).…”

Caloric restriction attenuates C57BL/6J mouse lung injury and extra-pulmonary toxicity induced by real ambient particulate matter exposure

“…A line of evidence has demonstrated that CR acts as a modulator of XREs and up-regulation of the expression of enzymes involved in phase I, phase II metabolism and xenobiotic transport in mouse liver [30,62,66]. CR led to an increase in microsomal enzyme activity of cytochrome P450 (CYP450), modifying phase I metabolism of environmental toxicants [31,32]. Notably, CR enhanced detoxi cation of environmental chemicals and reduced the formation of adducts through increasing the activity of phase II metabolizing enzymes, such as glutathione S-transferases (GSTs), uridine diphosphate glucuronosyltransferase (UGTs), and NAD(P)H: quinone oxidoreductase (NQOs) [33,67,68].…”

“…Previous studies have reported that CR could alter the expression and the activity of a wide range of xenobiotic metabolizing enzymes and transporters. The enhancement of CR-related detoxication of chemical carcinogens, such as a atoxin B 1 (AFB 1 ), benzo[a]pyrene (BaP), and 7,12-dimethylbenz(a)anthracene (DMBA), has been linked to the up-regulation of phase-I and phase-II metabolizing genes [30][31][32][33]. However, it remains unclear whether the synergistic effects are associated with metabolic activation (primarily phase I enzymes) and detoxi cation (primarily phase II enzymes), accelerating the clearance of PM-bound chemicals.…”

A Mouse Model of Severe Halothane Hepatitis Based on Human Risk Factors

“…Accordingly, consideration should be given to fasting as a potential contributor to risk for halothane hepatitis in humans. Fasting increases hepatic CYP2E1 expression and decreases hepatic glutathione stores in rodents (Qin et al, 2007), and this may reduce protection against reactive metabolites generated during oxidative metabolism of halothane. Treatment of guinea pigs with an inhibitor of glutathione biosynthesis increased covalent binding of reactive halothane intermediates and enhanced liver injury (Lind et al, 1992).…”