Dichloroethylene metabolism

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Dichloroethylene metabolism.

Dichloroethylene, a chemical used in the manufacturing of plastics, can cause pulmonary and hepatocellular injury. Mechanism of Dichloroethylene-induced injury involves cytochrome P-450-catalyzed metabolism of this compound resulting in formation of reactive intermediates, such as Dichloroacetaldehyde, Dichloroethylene epoxide, and 2-Chloroacetyl chloride, that bind covalently to bioactive macromolecules 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 of Dichloroethylene is primarily dependent upon availability of reduced glutathione for conjugation. Secondary metabolites are produced as the result of further conjugation reactions that result in the synthesis of S-(2,2-Dichloro-1-hydroxy)ethyl glutathione, 2-(S-Glutathionyl)acetyl glutathione, and 2-Chloroacetyl glutathione. Conjugation with glutathione catalyzed by Glutathione S-transferase A2 (GSTA2) [1], [5], [6].

References:

  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

  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

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