Effect of Long-Term Ethanol Pretreatment on the Metabolism of Dichloromethane to Carbon Monoxide in Rats

Wirkner, Kerstin; Damme, Britt; Poelchen, Wolfgang; Pankow, D

doi:10.1006/taap.1996.8077

Cited by 11 publications

(13 citation statements)

References 32 publications

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“…Rats receiving injected DCM (3 mol/kg i.p.) (Kim and Kim, 1996) or inhaled DCM (100 -500 ppm) (Wirkner et al, 1997) also exhibited a COHb level around 10 to 12%, which is the metabolism-delimited saturation level. The quantity of CO produced per mole of inhaled DCM in rats was about 0.7 to 0.8 mol (Andersen et al, 1994).…”

Section: E Use Of Prodrugs To Generate Carbon Monoxidementioning

confidence: 92%

“…The quantity of CO produced per mole of inhaled DCM in rats was about 0.7 to 0.8 mol (Andersen et al, 1994). The half-life of DCM in vivo is about 3 h, and CO released from DCM has a half-life of about 13 h (Wirkner et al, 1997;Sass et al, 2004).…”

Section: E Use Of Prodrugs To Generate Carbon Monoxidementioning

confidence: 98%

“…Six hours after administration of a single oral dose of DCM (6.2 mol/kg) to rats, the mean maximum COHb level of 9.3% was detected. This level was significantly enhanced by prior administration of benzene, toluene, o-and m-xylene, and p-xylene (Pankow et al, 1991) or long-term ethanol treatment (Wirkner et al, 1997). Rats receiving injected DCM (3 mol/kg i.p.)…”

Section: E Use Of Prodrugs To Generate Carbon Monoxidementioning

confidence: 99%

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Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications

Wang²

2005

Pharmacol Rev

853

741

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Section: E Use Of Prodrugs To Generate Carbon Monoxidementioning

confidence: 92%

Section: E Use Of Prodrugs To Generate Carbon Monoxidementioning

confidence: 98%

Section: E Use Of Prodrugs To Generate Carbon Monoxidementioning

confidence: 99%

See 1 more Smart Citation

Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications

Wang²

2005

Pharmacol Rev

853

741

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“…Unlike its chemical congeners, such as carbon tetrachloride and chloroform, that are potent hepatotoxins, the liver toxicity of this substance is negligible (Nitschke et al, 1988). Instead, DCM is metabolically converted to carbon monoxide (CO) by CYP2E1 (Guengerich et al, 1991;Kim and Kim, 1996;Wirkner et al, 1997), leading to elevation of blood carboxyhemoglobin (COHb) levels. Accordingly hypoxia due to a decrease in O 2 -carrying capacity constitutes a major toxicological problem associated with DCM exposure (Horowitz, 1986;Mahmud and Kales, 1999).…”

mentioning

confidence: 99%

Induction of Hepatic CYP2E1 by a Subtoxic Dose of Acetaminophen in Rats: Increase in Dichloromethane Metabolism and Carboxyhemoglobin Elevation

Kim

Seo²,

Jung³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Dichloromethane (DCM) is metabolically converted to carbon monoxide mostly by CYP2E1 in liver, resulting in elevation of blood carboxyhemoglobin (COHb) levels. We investigated the effects of a subtoxic dose of acetaminophen (APAP) on the metabolic elimination of DCM and COHb elevation in adult female rats. APAP, at 500 mg/kg i.p., was not hepatotoxic as measured by a lack of change in serum aspartate aminotransferase, alanine aminotransferase, and sorbitol dehydrogenase activities. In rats pretreated with APAP at this dose, the COHb elevation resulting from administration of DCM (3 mmol/kg i.p.) was enhanced significantly. Also blood DCM levels were reduced, and its disappearance from blood appeared to be increased. Hepatic CYP2E1-mediated activities measured with chlorzoxazone, p-nitrophenol, and p-nitroanisole as substrates were all induced markedly in microsomes of rats treated with APAP. Aminopyrine N-demethylase activity was also increased slightly, but significantly. Western blot analysis showed that APAP treatment induced the expression of CYP2E1 and CYP3A proteins. Neither hepatic glutathione contents nor glutathione S-transferase activity was changed by the dose of APAP used. The results indicate that, contrary to the well known hepatotoxic effects of this drug at large doses, a subtoxic dose of APAP may induce CYP2E1, and to a lesser degree, CYP3A expression. This is the first report that APAP can increase cytochrome P450 (P450)-mediated hepatic metabolism and the resulting toxicity of a xenobiotic in the whole animal. The pharmacological/toxicological significance of induction of P450s by a subtoxic dose of APAP is discussed.Acetaminophen (APAP), a widely used analgesic-antipyretic, may cause severe liver and kidney injuries at large or chronic doses. The APAP-mediated cellular injury is primarily initiated by metabolic conversion of this drug into a reactive intermediate, N-acetyl-p-benzoquinoneimine. It has been demonstrated that multiple forms of cytochrome P450 (P450) including CYP2E1, 1A2, and 3A4 are implicated in the activation of APAP to the reactive metabolite (Raucy et al., 1989;Patten et al., 1993;Zaher et al., 1998), but most investigators accept the fact that CYP2E1 has a principal role in the oxidative metabolism of this drug both in humans and rodents. The reactive metabolite is normally detoxified by conjugation with glutathione (GSH). Therefore, the hepatotoxicity of APAP is mainly dependent on the metabolic activities responsible for the activation of this drug and the effectiveness of GSH conjugation reaction.Dichloromethane (DCM, CH 2 Cl 2 ) is widely used in industry as a degreaser, as a solvent, as an extraction medium, and also as an important constituent of paint removers. Unlike its chemical congeners, such as carbon tetrachloride and chloroform, that are potent hepatotoxins, the liver toxicity of this substance is negligible (Nitschke et al., 1988). Instead, DCM is metabolically converted to carbon monoxide (CO) by CYP2E1 (Guengerich et al., 1991;Kim and Kim, 1996;Wi...

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“…1993a;Andersen et al 1994;Wirkner et al 1997). In addition, the gluthathione-transferase GSTM and GSTT isoforms metabolize styrene and dichloromethane, respectively (Andersen et ul.…”

Section: Discussionmentioning

confidence: 99%

In vitro Screening for Metabolic Interactions among Frequently Occurring Binary Mixtures of Volatile Organic Chemicals in Norwegian Occupational Atmosphere

Mortensen

Osvoll

Woldbæk

et al. 1998

Pharmacology & Toxicology

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Surveys of Norwegian industrial occupational atmosphere between 1983 to 1996, have identified the 12 most frequent occurring binary combinations of volatile organic chemicals. These combinations were tested in vitro for mutual inhibition or enhancement of metabolism by the head space vial equilibration technique with liver S9 obtained from in viva untreated or pretreated (with the binary mixture) rats. The in vitro system responded to in vivo pretreatment by increasing the metabolic rate of several potentially toxic organic chemicals such as toluene, xylene, styrene, and dichloromethane. In untreated liver S9, the metabolism of several of the tested binary pairs was inhibited when coexposed in vitro to their most prevalent follower as shown for instance for ethanol (with ethyl acetate), dichloromethane (with styrene) and mutually between toluene and xylene. This inhibitory effect disappeared, however, for several of the solvents when combined with the in vivo induced liver S9, a situation which may be the most relevant for occupational exposure. It is concluded that several metabolic interactions occur between low-molecular weight volatile chemicals found in occupational air. These are both inductive and inhibitory in nature and a further mechanistic evaluation including a higher number of differentiated dosage levels, must be performed before a possible health hazard can be confirmed or rejected for the investigated combinations.

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Effect of Long-Term Ethanol Pretreatment on the Metabolism of Dichloromethane to Carbon Monoxide in Rats

Cited by 11 publications

References 32 publications

Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications

Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications

Induction of Hepatic CYP2E1 by a Subtoxic Dose of Acetaminophen in Rats: Increase in Dichloromethane Metabolism and Carboxyhemoglobin Elevation

In vitro Screening for Metabolic Interactions among Frequently Occurring Binary Mixtures of Volatile Organic Chemicals in Norwegian Occupational Atmosphere

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