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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 kcal-food 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.

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 (CHCl3) and carbon tetrachloride (CCl4). The CYP2E1 content was significantly increased in 15 kcal-food 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 CHCl3 and CCl4, 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. CHCl3 was cleared by hepatic metabolism about 8-10 times faster than that of CCl4. Similarly, the areas under the blood concentration-time curve of CCl4 was as much as twice that of the corresponding CHCl3. In conclusion, when food was restricted to less than half of conventional amount, hepatic metabolism was affected and the hepatotoxicity induced by CCl4 or CHCl3 was augmented by, at least in part, CYP2E1 induction and GSH depletion. [ABSTRACT FROM AUTHOR]

Abstract: Background:: Voglibose is an α-glucosidase inhibitor used to decrease postprandial hyperglycemia in diabetic patients. Although clinical concern has not yet been raised, hepatic dysfunction has been reported in a few patients taking this drug. Method:: In the present study, we studied the effects of voglibose on the hepatotoxicity of carbon tetrachloride (CCl4) and acetaminophen (APAP) in rats, since both of these agents exert their effects through isoforms of cytochrome P450. Male Sprague–Dawley rats were given a daily ration (20g) of powdered chow diet containing 0, 2.5, 5.0 or 10.0mg/100g of voglibose. Three weeks later, the rats were challenged with either 0.50g/kg CCl4 orally or 0.75g/kg APAP intraperitoneally for biochemical examinations or killed for an in vivo metabolism study. Results:: Voglibose at these three experimental doses potentiated CCl4 and APAP hepatotoxicity, as evidenced by significantly increased levels of both plasma asparate transaminase (AST) and alanine transaminae (ALT). The glutathione (GSH) content was decreased while malondialdehyde (MDA) increased in the liver after CCl4 or APAP administration. Hepatic cytochrome P450 2E1 (CYP2E1) concentration was increased at doses of 5.0 and 10.0mg/100g of voglibose and its activity increased in the three voglibose dosage groups, while hepatic cytochrome P450 3A (CYP3A) and cytochrome P450 1A2 (CYP1A2) were only slightly changed at any dose. Conclusion:: Our study demonstrated that voglibose can potentiate CCl4 and APAP hepatotoxicity in rats by inducing hepatic CYP2E1. [Copyright &y& Elsevier]

Troglitazone (TRZ) is the first of a new group of oral antidiabetic drugs, the thiazolidinediones, and is proven to lower plasma glucose levels in patients with type 2 diabetes mellitus. However, the concern has been raised because of several reports, in which severe hepatic dysfunction leading to hepatic failure was demonstrated in a few patients receiving the drug. We studied the effects of TRZ on the hepatotoxicity of carbon tetrachloride (CCl4) and acetaminophen (APAP) in rats, both of which exert their toxic effects through bioactivation associated with cytochrome P450 3A (CYP3A) and 2E1 (CYP2E1).Male standard (Wistar/ST) and type 2 diabetic model (GK/Jal) rats were kept on a powdered chow diet containing 0, 100, 500 mg/kg/rat of TRZ. Three weeks later, the rats were either sacrificed for an in vitro metabolism study or challenged with 0.50 g/kg CCl4 p.o. or 0.75 g/kg APAP i.p.TRZ at 100 and 500 mg/kg/rat increased the CYP3A level as well as the testosterone 6β-hydroxylation activities in liver microsomes, but did not affect CYP2E1. TRZ also enhanced APAP hepatotoxicity, as evidenced by significantly increased levels of alanine aminotransferase, aspartate aminotransferase and α-glutathione S-transferase in the plasma of rats, and by significantly low hepatic glutathione concentration.Our study demonstrated that high doses of TRZ can enhance hepatotoxicity of APAP in Wistar/ST and GK/Jal by inducing hepatic CYP3A. [Copyright &y& Elsevier]