Cytochrome P450 2E1 (CYP2E1) is Essential for Acrylonitrile Metabolism to Cyanide: Comparative Studies Using CYP2E1-Null and Wild-Type Mice

Abstract

ABSTRACT:Acrylonitrile (AN) is a rodent carcinogen and suspected human carcinogen. Metabolism of AN proceeds via conjugation with glutathione or epoxidation via cytochrome P4502E1 (CYP2E1) to cyanoethylene oxide (CEO). It was hypothesized that CEO metabolism via epoxide hydrolase (EH) is the primary pathway for cyanide formation. The objective of this work is to assess the enzymatic basis of metabolism to cyanide. Male wild-type and CYP2E1-null mice received 0, 2.5, 10, 20, or 40 mg of AN/kg by gavage, and cyanide was measured in blood and tissues. CYP2E1 and EH expression were assessed using Western blot analyses. Present results demonstrated that cyanide concentrations in blood and tissues of AN-treated wild-type mice were higher at 1 versus 3 h, increased in a dose-dependent manner, and were significantly higher in AN-treated versus vehicle-treated mice. In contrast, cyanide concentrations in the blood and tissues of AN-treated CYP2E1-null mice were not statistically different from those of vehicle-treated mice. Furthermore, this work showed that EH is expressed in CYP2E1-null and wild-type mice. In conclusion, under the current experimental conditions using CYP2E1-null mice, current work demonstrated for the first time that CYP2E1-mediated oxidation is a prerequisite for AN metabolism to cyanide. Since earlier studies showed that CYP2E1 is the only enzyme responsible for AN epoxidation, it is concluded that AN metabolism to CEO is a prerequisite for cyanide formation, and this pathway is exclusively catalyzed by CYP2E1. Finally, this work confirmed that cyanide plays an essential role in the causation of the acute toxicity/mortality of AN.

Hesperidin, an antioxidant flavonoid, prevents acrylonitrile‐induced oxidative stress in rat brain

“…It was hypothesized that CEO metabolism via epoxide hydrolase is the primary pathway for cyanide formation [2]. Glutathione (GSH) conjugation has been shown to be depleted following ACN treatment in vivo and may decrease the antioxidant capacity of the cells resulting in an overall increase in intracellular reactive oxygen species (ROS) and oxidative damage [7][8][9].…”

“…Acrylonitrile (ACN) is a widely used monomer in the production of synthetic fibers, rubbers, plastics and as a chemical intermediate in the synthesis of a variety of products including antioxidants, pharmaceuticals, and dyes [1,2]. The important use of ACN in clinical practice is in the manufacture of high permeable dialysis tubings [3] and in the synthesis of artificial membrane to encapsulate Langerhans islets implants [4].…”

Role of CYP2E1-mediated metabolism in the acute and vestibular toxicities of nineteen nitriles in the mouse

“…Ensuing studies demonstrated that the CYP2E1 enzyme metabolizes a number of low molecular weight alkyl nitriles (Ghanayem et al, 1999) and is responsible for the initial metabolism of acrylonitrile leading to cyanide release (Wang et al, 2002;Chanas et al, 2003;El Hadri et al, 2005). However, the role of this or other metabolic routes in sensory effects remains poorly understood.…”

Acrylonitrile has Distinct Hormetic Effects on Acetylcholinesterase Activity in Mouse Brain and Blood that are Modulated by Ethanol

“…Ethanol pretreatment induces CYP 2E1 activity (Daiker et al 2000), which has been shown to play a critical role in the bioconversion of AN, promoting degradation of AN and the release of cyanide ions (Sumner et al 1999;Wang et al 2002).…”