Alterations in Dichloromethane-Induced Carboxyhemoglobin Elevation by Several Metabolic Modulators

이염화메탄에 의한 Carboxyhemogolbin 생성에 몇몇 대사활성조절제들이 미치는 영향

  • Published : 1995.12.01

Abstract

Several metabolic modulators on the generation of carbon monoxide (CO)from dichloromethane (DCM) was examined in adult female rats. It has been known that DCM is converted to CO by cytochrome P-450 or to carbon dioxide $(CO_2)$ by glutathione-dependent metabolic reaction. In rats treated with DCM (3 mmol/kg, ip) only, the carboxyhemoglobin (COHb) level reached a peak of approximately 10% 2 or 3 hr following the treatment. Disulfiram (300 mg/kg, ip) or allylsulfide (200 mg/kg, po), both known as a selective inhibitior for cytochrome P-450 2E1, blocked the increase in COHb concentratlons almost completely suggesting that the metabolic conversion of DCM to CO is mediated by the activity of this specific type of isozyme. YH439 (125 or 250 mg/kg, po), a potential hepatoprotective agent, decreased the COHb elevation as well indicating that this chemical is a potent inhibitor for 2E1. In rats treated with pyrazine (200 mg/kg, ip) 18 hr prior to DCM the peak COHb concentration was decreased by approximately 3 or 4%. However, pretreatment of rats with pyrazine either 24 or 48 hr before DCM increased the peak COHb concentration significantly compared to the rats treated with DCM only. The results in the present study strongly suggest that the generation of CO from DCM depends on the 2E1 activity and that the pharmacological and/or toxicological action of YH439 or pyrazine in animals or human is associated with its effect on this isozyme.

Keywords

References

  1. Cancer Res. v.48 Effect of diallylsulfide on rat microsomal nitrosamine and other monooxygenase activities Brady,J.F.;Li,D.;Ishzaki,H.;Yang,C.S.
  2. Toxicol. Appl. Pharmacol. v.108 Effects of disulfiram on hepatic P450IIE1, other microsomal enzymes, and hepatotoxicity in rats Brady,J.F.;Xiao,F.;Wang,M.H.;Li,Y.;Ning,S.M.;Grapac,J.M.;Yang,C.S.
  3. M.S.Thesis Effects of YH439 on the expression of rat hepatic CYP 2E1, microsomal epoxide hydrolase, glutathione S-transferase Choi,E.Y.
  4. Chem. Res. Toxicol. v.4 Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects Guengerich,F.P.;Kim.D.H.;Iwasaki,M.
  5. Fundam. Appl. Toxicol. v.6 The effect of anunusual workshift on chemical toxicity I. Studies on the expourse of rats and mice to dichloromethane Kim,Y.C.;Carlson,G.P.
  6. Drug Metab. Dispos. v.2 Metabolism of dihalomethane to carbon monoxide I. In vivo studies Kubic,V.L.;Anders,M.W.;Engel,R.P.;Barloco,C.H.
  7. Drug Metab. Dispos. v.3 Metabolism of dihalomethane to carbon monoxide II. In vivo studies Kubic,V.L.;Anders,M.W.
  8. Biochem. Pharmacol. v.27 Metabolism of dihalomethane to carbon monoxide III. Studies on the mechanism of reaction Kubic,V.L.;Anders,M.W.
  9. Res. Commun. Chem. Path. Pharmacol. v.32 Effects of intermittent dichlormethane inhalation on the blood carboxyhemoglobin concentration and drug metabolizing enzymes in rants Kurppa,K.;Vainio,H.
  10. M.S. Thesis Effect of allylsulfides on the expressio of cytochrome P4502E1, glutathione Stransferase, microsomal epoxide hydrolase Kwak,M.K.
  11. Toxicologist v.11 Thiazole, pyridazine and pyrazine induction of glutathione Stransferase in rats Novak,R.F.;Kim,S.G.;Brooks,S.C.;Primito,T.;Salinas,F.M.;Novak,J.C.
  12. Clin. Chem. v.25 Spectrophotometric measurement of COHb and methemoglobin in blood Redkey,F.L.;Hill,T.A.;Robertson,R.F.
  13. Toxicology v.68 Influence of dichloromethane to carbon monoxide in rats Pankow,D.P.;Matsciner,F.;Weingmann,H.J.
  14. Science v.176 Carboxyhemoglobin elevation after exposure to methylene chloride Stewart,R.D.;Fisher,T.N.;Hosko,M.J.;Peterson,J.E.;Baretta,E.D.;Dodd,H.C.
  15. Pharmacokinetics of YH439, Ph.D. Thesis Yoon,W.H.