The pharmacokinetics of inhaled methylene chloride in rats

McKenna, Michael J.; Zempel, J.A.; Braun, Werner

doi:10.1016/0041-008x(82)90356-8

Cited by 50 publications

(10 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CYP2E1 was shown to be the major subtype of the cytochrome P450 family responsible for the metabolic conversion of DCM to CO (Guengerich et al, 1991). This pathway has a high affinity for DCM with limited capacity (McKenna et al, 1982). The alternative metabolic pathway of DCM is a reaction with GSH mediated by GSTs, especially the Theta class GST, which produces CO 2 via S-chloromethyl-GSH (GSCH 2 Cl) and formaldehyde (Blocki et al, 1994;Mainwaring et al, 1996).…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…The work of these investigators unveiled the extensive nonlinear behaviors associated with saturation of metabolism that frequently occurred at high-doses used in toxicology studies in test animals. Among the important classes of chemicals studied by these investigators were herbicides (Sauerhoff et al, 1976(Sauerhoff et al, , 1977, solvents (McKenna et al, 1982), industrial monomers (McKenna et al, 1978a,b), and hydrocarbons (Young et al, 1979;Ramsey et al, 1980). This work generally took the form of careful, detailed collection of biological data on time-course blood levels or excretion patterns at various dosage levels.…”

Section: A Historical Perspectivementioning

confidence: 99%

Toxicokinetic modeling and its applications in chemical risk assessment

Andersen

2003

Toxicology Letters

158

View full text Add to dashboard Cite

“…The kinetics of inhaled methylene chloride in male Sprague Dawley rats (250 g) were studied after exposure to 174,1740, and 5220 mg/m s for 6 h (McKenna, Zempel, and Braun, 1982). Food and water were provided ad libitum except during the inhalation exposure.…”

Section: Interspeoes Differences In Inhalation Absorption Methylene Cmentioning

confidence: 99%

Interspecies comparison of kinetic data of chlorinated chemicals of potential relevance to risk assessment

Skowronski

Abdel‐Rahman

1997

Human and Ecological Risk Assessment: An International Journal

View full text Add to dashboard Cite

Most noncancer risk assessments focus on the NOAEL (the no observed adverse effect level), an external dose. However, the internal dose considers the ongoing kinetics between chemical intake and target site and will provide a better dose-response relationship. The purpose of this study was to conduct a literature search for kinetic parameters in animals and humans administered chlorinated chemicals by the oral or inhalation routes. Frequendy used industrial solvents as well as pesticides were evaluated. Animal to human kinetic ratios were calculated and compared to the proposed kinetic default subfactors of Renwick for oral chemicals and of the USEPA for inhaled compounds. Kinetic default subfactors were then replaced by data-derived values and the interspecies factors were recalculated. Seventy percent of data-derived kinetic ratios were lower than proposed default values. Thus, incorporation of internal dose can reduce uncertainty in animal-human extrapolation. Furthermore, metabolites should be examined because for some compounds, species differences in toxicity may be due to metabolites.

show abstract

The pharmacokinetics of inhaled methylene chloride in rats

Cited by 50 publications

References 6 publications

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

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

Toxicokinetic modeling and its applications in chemical risk assessment

Interspecies comparison of kinetic data of chlorinated chemicals of potential relevance to risk assessment

Contact Info

Product

Resources

About