Selective Inhibition of Cytochrome P450 2E1 in Vivo and in Vitro withtrans-1,2-Dichloroethylene

Abstract

The effect of trans-1,2-dichloroethylene (DCE), an inhibitor of cytochrome P450 (P450) 2E1, on the catalytic activities and total content of hepatic P450 was determined in vivo and in vitro. Hepatic microsomes were prepared from groups of rats prior to dosing and at 2, 5, 12, and 24 h postdosing, and total P450 content and the activities of P450 1A2, P450 2A1, P450 2B, P450 2C6, P450 2C11, P450 2D1, P450 2E1, and P450 3A were determined. The lowest dose of DCE that yielded maximal inactivation of P450 2E1 was found to be 100 mg/kg. Significant decreases in total content of P450 or the activities of P450 1A2, P450 2A1, P450 2B, P450 2C6, P450 2C11, P450 2D1, and P450 3A were not observed during the 24 h following administration of DCE (100 mg/kg ip), but P450 2E1 activity was diminished about 65% at 2 and 5 h after DCE treatment and returned to control levels at 24 h. Additionally, there was little or no significant effect on the activities of hepatic cytosolic alcohol dehydrogenase or mitochondrial or microsomal aldehyde dehydrogenases 5 h postdosing. DCE showed the same selectivity for P450 inactivation in vitro, and P450 2E1 activity was inhibited by >80% without affecting the other isozymes. However, DCE (5 mM) also proved to be a good competitive inhibitor of the probe activities of P450 1A2 and P450 2C6. The in vivo inhibition of P450 2E1 was accompanied by decreases in the levels of the immunoreactive protein, and an additional immunoreactive band appeared at ca. 30 kDa in the Western blot of microsomes from DCE-treated rats, possibly arising from proteolytic degradation of P450 2E1 protein after covalent modification by the inhibitor. DCE is an effective, relatively nontoxic inhibitor of P450 2E1 in vivo and in vitro that has greater selectivity than other agents currently used.

CYP2E1 and oxidative liver injury by alcohol

“…Actually, natural agents inhibiting CYP2E1, including dially sulfide (from garlic) mentioned above, phenylethyl isothiocyanate and sulforaphane (present in cruciferous vegetables) and bergamottin (found in the essential oils of grapefruit and certain oranges) have been proposed as possible candidates for minimizing the ethanol-induced hepatotoxicity (225). In addition, trans-1,2-dichloroethylene (DCE) was reported to be a selective inhibitor of CYP2E1 (226).…”

Reduced Systemic Toxicity and Preserved Vestibular Toxicity Following Co-treatment with Nitriles and CYP2E1 Inhibitors: a Mouse Model for Hair Cell Loss

“…in 6 ml/kg of corn oil; DAS acts as a competitive inhibitor of CYP2E1 and is also metabolized to suicide inhibitors of the same enzyme. Another suicide inhibitor selective for CYP2E1, TDCE (Lilly et al 1998;Mathews et al 1998), was administered i.p. in 6 ml/kg of corn oil.…”

“…The use of three doses was chosen to ensure the maximal effect of TDCE over the time period of allylnitrile ototoxicity, according to data in the literature (Mathews et al 1998). …”

Ethanol Suppresses Ureagenesis in Rat Hepatocytes

“…Contribution of Cytochrome P450 2E1 to Ethanol-mediated Suppression of Ureagenic Respiration-To assess the importance of ethanol metabolism via CYP450 2E1 in ethanol-induced suppression of ureagenic respiration, hepatocytes were pretreated with trans-1,2-dichloroethylene (DCE, 5 mM), a CYP450 2E1 inhibitor (38), before ethanol addition. DCE did not affect ureagenic respiration in the absence of ethanol (Fig.…”