Comment on M.V. Evans and J.C. Caldwell: evaluation of two different metabolic hypotheses for dichloromethane toxicity using physiologically based pharmacokinetic modeling of in vivo gas uptake data exposure in female B6C3F1 mice, Toxicol. Appl. Pharmacol., 244, 280-290, 2010.

摘要

M.V. Evans and J.C. Caldwell (Evaluation of two different metabolic hypotheses for dichloromethane toxicity using physiologically based pharmacokinetic modeling of in vivo gas uptake data exposure in female B6C3F1 mice, Toxicol. Appl. Pharmacol, 244, 280-290, 2010) refute well-established metabolic pathways and PBPK models for dichloromethane (DCM) metabolism in favor of a metabolic-switch model. The metabolic-switch model hypothesizes two oxidative pathways for DCM bioactivation via two-active sites for cytochrome P450 2E1 (CYP2E1) oxidation with differing affinities. Evans and Caldwell then summarily dismiss a role for glutathione transferases (GSTs) in DCM bioactivation. The conclusions of Evans and Caldwell stand in stark contrast to abundant evidence for both low K_m CYP2E1 and high K_m GST in DCM metabolism and to the evidence that supports GST-catalyzed DCM bioactivation as the key mode of action for DCM carcinogenicity in mice.