Acetaminophen hepatotoxicity: An update

McClain, Craig J.; Price, Seth; Barve, Shirish; Devalarja, Radhika; Shedlofsky, Steven I.

doi:10.1007/s11894-999-0086-3

Cited by 81 publications

(46 citation statements)

References 46 publications

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“…Abnormally high AST, and especially ALT, point to hepatocyte damage (Herlong, 1994;Ozer et al, 2008). Higher elevations in ALT than AST are seen in drug-induced liver injury (McClain et al, 1999) and fatty liver disease (Roberts, 2005), whereas greater increases in AST than in ALT are seen in drug-induced kidney toxicity (Mazer and Perrone, 2008) or rhabdomyolysis (McKinnell and Tayek, 2009).…”

Section: Downloaded Frommentioning

confidence: 99%

Organ-Specific Roles of CYP1A1 during Detoxication of Dietary Benzo[a]pyrene

Shi¹,

Dragin²,

Gálvez-Peralta³

et al. 2010

Mol Pharmacol

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Polycyclic aromatic hydrocarbons (PAHs) are widely distributed environmental toxicants derived from sources that include cigarette smoke, petroleum distillation, gas-and diesel-engine exhaust, and charcoal-grilled food. The gastrointestinal tract is the principal route of PAH exposures, even when inhaled. The most thoroughly studied prototype of PAHs is benzo[a]pyrene (BaP), well known to be toxic, mutagenic, and carcinogenic in various tissues and cell types. This lab has previously shown that Cyp1a1(Ϫ/Ϫ) global knockout mice treated by oral administration of BaP die at 28 to 32 days with immunosuppression, whereas wild-type mice remain healthy for 1 year on high BaP doses (125 mg/kg/day). Thus, for oral BaP, CYP1A1 is more important in detoxication than in metabolic activation. After several days of oral BaP, we found surprisingly low CYP1A1 levels in liver, compared with that in small intestine; we postulated that this finding might reflect efficient detoxication of oral BaP in proximal small intestine such that significant amounts of the inducer BaP no longer reach the liver. In the present study, many parameters were therefore compared in wild-type, Cyp1a1(Ϫ/Ϫ) global knockout, intestinal epithelial cell-specific Cyp1a1 knockout, and hepatocyte-specific Cyp1a1 knockout mice as a function of long-term oral exposure to BaP. The peak of CYP1A1 (mRNA, protein) expression in liver occurred at 12 h, whereas highly induced CYP1A1 in small intestine persisted throughout the 30-day experiment. Hepatocyte-specific Cyp1a1 knockout mice remained as healthy as wild-type mice; intestinal epithelial cell-specific Cyp1a1 knockout mice behaved like Cyp1a1(Ϫ/Ϫ) mice, dying with immunosuppression ϳ30 days on oral BaP. We conclude that small intestine CYP1A1, and not liver CYP1A1, is critically important in oral BaP detoxication.

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Section: Downloaded Frommentioning

confidence: 99%

Organ-Specific Roles of CYP1A1 during Detoxication of Dietary Benzo[a]pyrene

Shi¹,

Dragin²,

Gálvez-Peralta³

et al. 2010

Mol Pharmacol

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“…The formation of oxygen radicals has been shown to lead to GSH and protein oxidation and the peroxidation of membrane lipids. Thus, TGZ had the potential to act via classical mechanisms and be a simple, intrinsic hepatotoxin similar to acetaminophen (26).…”

Section: Potential Mechanisms Of Toxicity Involving the Formation Of mentioning

confidence: 99%

Mechanisms of Troglitazone Hepatotoxicity

Smith¹

2003

Chem. Res. Toxicol.

183

117

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“…We hypothesize that the human CYP2E1-GAS element is one part of a negative feedback regulatory mechanism to limit the intracellular pool of CYP2E1 enzyme and thus limit the accumulation of reactive metabolic intermediates. Several substrates of this enzyme are initially bioactivated to reactive intermediates (Guengerich et al, 1991) and initiate an aseptic inflammatory response (McClain et al, 1999). Aseptic inflammation causes suppression of multiple cytochrome P450 enzymes, including CYP2E1 (Siewert et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Suppression of Cytochrome P450 2E1 Promoter Activity by Interferon-γ and Loss of Response Due to the -71G>T Nucleotide Polymorphism of the CYP2E1^*7B Allele

Qiu¹,

Linder²,

Antonino-Green³

et al. 2003

J Pharmacol Exp Ther

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The CYP2E1*7B allele is defined by two nucleotide sequence polymorphisms, Ϫ71GϾT and Ϫ333TϾA. The CYP2E1 promoter sequence flanking the Ϫ71G nucleotide is consistent with a ␥-interferon activated sequence. Inflammation and interferon (IFN)-␥ suppress expression of CYP2E1 in vivo; however, the exact mechanism is not known. The objectives of this study were to determine whether the CYP2E1 promoter is regulated by IFN-␥ and to examine the influence of the nucleotide substitutions on this function. Treatment of HepG2 cells with IFN-␥, after transient transfection with a luciferase reporter gene bearing the native CYP2E1 (Ϫ71G) promoter sequence resulted, in a dose-dependent reduction of luciferase activity. In contrast, no suppression was observed in cells transfected with the *7B allele promoter (Ϫ333A and Ϫ71T) nor a CYP2E1 plasmid containing only the Ϫ71T polymorphism. These data indicate that IFN-␥ suppresses native CYP2E1 promoter activity and that the Ϫ71G is critical for this response.

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Acetaminophen hepatotoxicity: An update

Cited by 81 publications

References 46 publications

Organ-Specific Roles of CYP1A1 during Detoxication of Dietary Benzo[a]pyrene

Organ-Specific Roles of CYP1A1 during Detoxication of Dietary Benzo[a]pyrene

Mechanisms of Troglitazone Hepatotoxicity

Suppression of Cytochrome P450 2E1 Promoter Activity by Interferon-γ and Loss of Response Due to the -71G>T Nucleotide Polymorphism of the CYP2E1^*7B Allele

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Acetaminophen hepatotoxicity: An update

Cited by 81 publications

References 46 publications

Organ-Specific Roles of CYP1A1 during Detoxication of Dietary Benzo[a]pyrene

Organ-Specific Roles of CYP1A1 during Detoxication of Dietary Benzo[a]pyrene

Mechanisms of Troglitazone Hepatotoxicity

Suppression of Cytochrome P450 2E1 Promoter Activity by Interferon-γ and Loss of Response Due to the -71G>T Nucleotide Polymorphism of the CYP2E1*7B Allele

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Suppression of Cytochrome P450 2E1 Promoter Activity by Interferon-γ and Loss of Response Due to the -71G>T Nucleotide Polymorphism of the CYP2E1^*7B Allele