Evaluation of two different metabolic hypotheses for dichloromethane toxicity using physiologically based pharmacokinetic modeling for in vivo inhalation gas uptake data exposure in female B6C3F1 mice
- National Center for Environmental Assessment -Washington Division, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States)
Dichloromethane (DCM, methylene chloride) is a lipophilic volatile compound readily absorbed and then metabolized to several metabolites that may lead to chronic toxicity in different target organs. Physiologically based pharmacokinetic (PBPK) models are useful tools for calculation of internal and target organ doses of parent compound and metabolites. PBPK models, coupled with in vivo inhalation gas-uptake data, can be useful to estimate total metabolism. Previously, such an approach was used to make predictions regarding the metabolism and to make subsequent inferences of DCM's mode of action for toxicity. However, current evidence warrants re-examination of this approach. The goal of this work was to examine two different hypotheses for DCM metabolism in mice. One hypothesis describes two metabolic pathways: one involving cytochrome P450 2E1 (CYP2E1) and a second glutathione (GSH). The second metabolic hypothesis describes only one pathway mediated by CYP2E1 that includes multiple binding sites. The results of our analysis show that the in vivo gas-uptake data fit both hypotheses well and the traditional analysis of the chamber concentration data is not sufficient to distinguish between them. Gas-uptake data were re-analyzed by construction of a velocity plot as a function of increasing DCM initial concentration. The velocity (slope) analysis revealed that there are two substantially different phases in velocity, one rate for lower exposures and a different rate for higher exposures. The concept of a 'metabolic switch,' namely that due to conformational changes in the enzyme after one site is occupied - a different metabolic rate is seen - is also consistent with the experimental data. Our analyses raise questions concerning the importance of GSH metabolism for DCM. Recent research results also question the importance of this pathway in the toxicity of DCM. GSH-related DNA adducts were not formed after in vivo DCM exposure in mice and DCM-induced DNA damage has been detected in human lung cultures without GSH metabolism. In summary, a revised/updated metabolic hypothesis for DCM has been examined using in vivo inhalation data in mice combined with PBPK modeling that is consistent with up-to-date models of the active site for CYP2E1 and suggests that this pathway is the major metabolizing pathway for DCM metabolism.
- OSTI ID:
- 21344930
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 244, Issue 3; Other Information: DOI: 10.1016/j.taap.2010.01.018; PII: S0041-008X(10)00043-8; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
BIOLOGICAL PATHWAYS
CONFORMATIONAL CHANGES
DNA ADDUCTS
DNA DAMAGES
EVALUATION
GLUTATHIONE
HYPOTHESIS
IN VIVO
INHALATION
KINETICS
LUNGS
MEN
METABOLISM
METABOLITES
METHYLENE CHLORIDE
MICE
RADIATION DOSES
SIMULATION
TOXICITY
ADDUCTS
ANIMALS
BODY
DOSES
DRUGS
INTAKE
MALES
MAMMALS
MAN
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANS
PEPTIDES
POLYPEPTIDES
PRIMATES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RESPIRATORY SYSTEM
RESPONSE MODIFYING FACTORS
RODENTS
VERTEBRATES