Carbon Monoxide Generation from Trihalomethane Metabolism in Rats

Abstract

Carboxyhaemoglobin (COHb) formation in rats after oral administration of trichloromethane (TCM), bromodi chloromethane (BDCM), chlorodibromomethane (CDBM) and tribromomethane (TBM) increased in the order TCM < BDCM < CDBM < TBM. The trihalomethanes are sub strates for cytochrome P₄₅₀ 2E1 (CYP2E1) and cyto chromes P₄₅₀ 2B1/2 (CYP2B1/2) as shown by: (a) the inhibi tion of COHb formation due to simultaneous administra tion of CDBM or TBM and diethyldithiocarbamate, an inhibitor of CYP2E1, and (b) the initially higher levels of COHb after gavage of CDBM or TBM in rats pretreated with isoniazid, an inducer of CYP2E1, or pretreated with phenobarbital, an inducer of CYP281/2. There is an en hancement of the COHb level after daily administration of CDBM or TBM for 7 days in comparison to a single gav age, but the COHb levels were not higher due to chronic intake of CDBM with the drinking water (2.4 μmol.l^-1) in comparison to the basic levels, measured during 26 weeks.

Keywords

Carboxyhaemoglobin Trihalomethanes Oxidative metabolism CYP2E1

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References

Pankow D. : Carbon monoxide formation due to metabolism of xenobiotics; in Penney DG (ed): Carbon Monoxide. Boca Raton, CRC Press 1996, pp 25-43.

Who/Iarc : Chlorinated Drinking-Water; Chlorination By-Products; Some Other Halogenated Compounds; Cobalt and Cobalt Compounds . IARC Monogr 52. Lyon, 1991.

Pohl LR , Brooshan B. , Whittacker NF , Krishna G. : Phosgene: A metabolite of chloroform. Biochem Biophys Res Commun 1977 ;79:684-691.

Testai E. , Di Marzio S. , Vittozzi L. : Multiple activation of chloroform in hepatic microsomes from uninduced B6C3F1 mice. Toxicol Appl Pharmacol 1990;104:496-503.

Tomasi A. , Albano E. , Biasi F. , Slater TF , Vannini V. , Dianzani MU : Activation of chloroform and related trihalomethanes to free radical intermediates in isolated hepatocytes and in the rat in vivo as detected by the ESPR-spin trapping technique. Chem Biol Interact 1985 ; 55:303-316.

Nakajima T. , Elovaara E. , Okino T. , Gelboin HV , Klockars M. , Riihimäki V. , Aoyama T. , Vainio H. : Different contribution of cytochrome P4502E1 and P4502B1/2 to chloroform hepatotoxicity in rat. Toxicol Appl Pharmacol 1995;133:215-222.

Stevens JL , Anders MW : Metabolism of halo-forms to carbon monoxide. IV. Studies on the reaction mechanism in vivo. Chem Biol Interact 1981;37:365-374.

Anderson ME : Determination of glutathione and glutathione disulfide in biological samples . Methods Enzymol 1985;113:548-555.

Schmidt P (ed): Biologische Kontrollmethoden in der Arbeitsmedizin. Berlin, Volk & Gesundheit, 1988, pp 345-346.

10.

Lehnebach A. , Kuhn C. , Pankow D. : Dichloromethane as an inhibitor of cytochrome c oxidase in different tissues of rats. Arch Toxicol 1995;69:180-184.

11.

Pankow D. , Weise M. , Hoffmann P. : Effect of isoniazid or phenobarbital pretreatment on the metabolism of dihalomethanes to carbon monoxide. Pol J Occup Med Environ Health 1992; 5:245-250.

12.

Brady JF , Xiao F. , Wang M-H. , Li Y. , Ning SM , Gapac JM , Yang CS : Effect of disulfiram on hepatic P450 IIE1, other microsomal enzymes, and hepatotoxicity in rats. Toxicol Appl Pharmacol 1991;108:366-373.

13.

Guengerich FP , Kim DH , Iwasaki M. : Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight suspects. Chem Res Toxicol 1991;4:168-179.

14.

Ryan DE , Koop DR , Thomas PE , Coon MJ , Levin W. : Evidence that isoniazid and ethanol induce the same microsomal cytochrome P-450 in rat liver, an isozyme homologous to rabbit liver cytochrome P-450 isozyme 3a. Arch Biochem Biophys 1986;246:633-644. 15 Pankow D. , Damme B. , Wünscher U. , Bergmann K. : Chlorodibromo-methane metabolism to bromide and carbon monoxide in rats. Arch Toxicol 1997;71:203-210.

15.

Koop DR : Hydroxylation of p-nitrophenol by rabbit ethanol-inducible cytochrome P450 isozyme 3a. Mol Pharmacol 1986;29:399-404.

16.

Ahmed AE , Kubic VL , Stevens JL , Anders MW : Halogenated methanes: Metabolism and toxicity. Fed Proc 1980;39:3150-3155.