当前位置： SCI文献检索 > BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY期刊下所有文献 > Contrasting changes in phase I and phase II metabolism of acetaminophen in male mice pretreated with carbon tetrachloride.

Contrasting changes in phase I and phase II metabolism of acetaminophen in male mice pretreated with carbon tetrachloride.

Abstract：

:Effect of carbon tetrachloride (CCl(4)) pretreatment on the biotransformation and elimination of acetaminophen were examined in male mice. A 24 hr initial dose of CCl(4) (0.05 ml/kg, intraperitioneally) reduced the induction of hepatotoxicity resulting from acetaminophen treatment (350 mg/kg, intraperitoneally) as determined by changes in serum alanine and aspartate aminotransferase, and sorbitol dehydrogenase activities. Acetaminophen and the major metabolites in plasma were monitored for 12 hr following acetaminophen treatment. CCl(4) pretreatment decreased the plasma concentrations of acetaminophen-cysteine and acetaminophen-mercapturate, but acetaminophen-glucuronide and acetaminophen-sulfate were increased significantly. The elimination of the parent drug from plasma was not affected by CCl(4). In urine collected for 24 hr, the concentrations of acetaminophen-sulfate and acetaminophen-glucuronide were increased by 84% and 33%, respectively, whilst acetaminophen-cysteine and acetaminophen-mercapturate were reduced to approximately one third of control. Expression of cytochrome P450 (CYP) isozymes was determined using antibodies of 2E1 and 1A2 as probes. CYP2E1 and 1A2 expressions were decreased significantly by CCl(4). Likewise, CCl(4) treatment reduced the microsomal p-nitrophenol hydroxylase and p-nitroanisole O-demethylase activities to less than one third of control. The results indicate that, although CCl(4) reduces the generation of thioether conjugates of acetaminophen by decreasing the CYP activities, inhibition of the oxidative metabolism of acetaminophen is counterbalanced by the enhancement of conjugate formation via the glucuronide and sulfate pathways, resulting in elimination of the drug at a rate equivalent to that in normal mice. It is suggested that liver injury in patients may not warrant a mandatory reduction of drug doses extensively inactivated via phase II reactions.

journal_name

Basic Clin Pharmacol Toxicol

journal_title

Basic & clinical pharmacology & toxicology

authors

Yim HK,Jung YS,Kim SY,Kim YC

doi

10.1111/j.1742-7843.2006.pto_308.x

subject

Has Abstract

pub_date

2006-02-01 00:00:00

pages

225-30

issue

eissn

1742-7835

issn

1742-7843

pii

PTOpto_308

journal_volume

pub_type

杂志文章

在线工具

Contrasting changes in phase I and phase II metabolism of acetaminophen in male mice pretreated with carbon tetrachloride.