RT Journal Article SR Electronic T1 Mechanisms of Circadian Rhythmicity of Carbon Tetrachloride Hepatotoxicity JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 273 OP 281 DO 10.1124/jpet.300.1.273 VO 300 IS 1 A1 James V. Bruckner A1 Raghupathy Ramanathan A1 K. Monica Lee A1 Srinivasa Muralidhara YR 2002 UL http://jpet.aspetjournals.org/content/300/1/273.abstract AB The toxicity of carbon tetrachloride (CCl4) and certain other chemicals varies over a 24-h period. Because the metabolism of some drugs follows a diurnal rhythm, it was decided to investigate whether the hepatic metabolic activation of CCl4 was rhythmic and coincided in time with maximum susceptibility to CCl4 hepatotoxicity. A related objective was to test the hypothesis that abstinence from food during the sleep cycle results in lipolysis and formation of acetone, which participates in induction of liver microsomal cytochrome P450IIE1 (CYP2E1), resulting in a diurnal increase in CCl4 metabolic activation and acute liver injury. Groups of fed and fasted male Sprague-Dawley rats were given a single oral dose of 800 mg of CCl4/kg at 2- to 4-h intervals over a 24-h period. Serum enzyme activities, measured 24 h post dosing as indices of acute liver injury, exhibited distinct maxima in both fed and fasted animals dosed with CCl4 near the beginning of their dark/active cycle. Blood acetone, hepatic CYP2E1 activity, and covalent binding of14CCl4/metabolites to hepatic microsomal proteins in untreated rats fed ad libitum followed circadian rhythms similar to that of susceptibility to CCl4. Parallel fluctuations of greater amplitude were seen in rats fasted for 24 h. Hepatic glutathione levels were lowest at the time of greatest susceptibility to CCl4. Acetone dose-response experiments showed high correlations between blood acetone levels, CYP2E1 induction, and CCl4-induced liver injury. Pretreatment with diallyl sulfide suppressed CYP2E1 and abolished the circadian rhythmicity of susceptibility to CCl4. These findings provide additional support for acetone's physiological role in CYP2E1 induction and for CYP2E1's role in modulating CCl4chronotoxicity in rats. VOCsvolatile organic compoundsP450cytochrome P450CYP2E1cytochrome P450IIE1GSHglutathioneS-DSprague-DawleyDASdiallyl sulfideALTalanine aminotransferaseSDHsorbitol dehydrogenaseICDisocitrate dehydrogenaseAUCarea under the curveGCgas chromatographNPSHnonprotein sulfhydrylGSHPxglutathione peroxidasePNP p-nitrophenol4-NC4-nitrocatecholβHBβ-hydroxybutyrateAAacetoacetate