Dichloroethylene metabolism

Dichloroethylene metabolism.

Dichloroethylene, a chemical used in the manufacturing of plastics, can causepulmonary and hepatocellular injury. Mechanism of Dichloroethylene-induced injuryinvolves cytochrome P-450-catalyzed metabolism of this compound resulting in formation ofreactive intermediates, such as Dichloroacetaldehyde, Dichloroethyleneepoxide, and 2-Chloroacetyl chloride, that bind covalently to bioactivemacromolecules in liver. Cytochrome P450, family 2, subfamily F, polypeptide 1 (CYP2F1 ) and Cytochrome P450, family 2, subfamily E, polypeptide 1 ( CYP2E1) are involved in oxidative metabolism of Dichloroethylene [1],[2], [3], [4]. Detoxification ofDichloroethylene is primarily dependent upon availability of reduced glutathionefor conjugation. Secondary metabolites are produced as the result of further conjugationreactions that result in the synthesis of S-(2,2-Dichloro-1-hydroxy)ethylglutathione, 2-(S-Glutathionyl)acetyl glutathione, and 2-Chloroacetylglutathione. Conjugation with glutathione catalyzed by Glutathione S-transferase A2 ( GSTA2 ) [5], [6], [1].

1. Forkert PG
   In vivo formation and localization of 1,1-dichloroethylene epoxide in murine liver: identification of its glutathione conjugate 2-S-glutathionyl acetate. The Journal of pharmacology and experimental therapeutics 1999 Sep;290(3):1299-306
2. Forkert PG
   Mechanisms of 1,1-dichloroethylene-induced cytotoxicity in lung and liver. Drug metabolism reviews 2001 Feb;33(1):49-80
3. Simmonds AC, Ghanayem BI, Sharma A, Reilly CA, Millen B, Yost GS, Forkert PG
   Bioactivation of 1,1-dichloroethylene by CYP2E1 and CYP2F2 in murine lung. The Journal of pharmacology and experimental therapeutics 2004 Sep;310(3):855-64
4. Simmonds AC, Reilly CA, Baldwin RM, Ghanayem BI, Lanza DL, Yost GS, Collins KS, Forkert PG
   Bioactivation of 1,1-dichloroethylene to its epoxide by CYP2E1 and CYP2F enzymes. Drug metabolism and disposition: the biological fate of chemicals 2004 Sep;32(9):1032-9
5. Dowsley TF, Forkert PG, Benesch LA, Bolton JL
   Reaction of glutathione with the electrophilic metabolites of 1,1-dichloroethylene. Chemico-biological interactions 1995 Apr 14;95(3):227-44
6. Dowsley TF, Reid K, Petsikas D, Ulreich JB, Fisher RL, Forkert PG
   Cytochrome P-450-dependent bioactivation of 1,1-dichloroethylene to a reactive epoxide in human lung and liver microsomes. The Journal of pharmacology and experimental therapeutics 1999 May;289(2):641-8