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Mutagenic and alkylating metabolites of halo-ethylenes, chlorobutadienes and dichlorobutenes produced by rodent or human liver tissues

Evidence for oxirane formation by P450-linked microsomal mono-oxygenases

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Abstract

Mutagenicity, expressed as the number of his + revenants per μmole of test compound per hour of exposure, was estimated in two strains of S. typhimurium in the presence of a postmitochondrial mouse-liver supernatant, following exposure to vapours of one of a series of halo-olefins. Their activity was in the following descending order: 3,4-dichlorobutene-1 > 1-chlorobutadiene (technical grade) > 2-chlorobutadiene > vinyl bromide > vinylidene chloride > vinyl chloride; marginal mutagenicity was detected in the presence of 1,1,2-trichloroethylene and 1,1-difluoroethylene, and none with tetrachloroethylene and vinyl acetate. Liver fractions from humans converted vinyl chloride, vinyl bromide, vinylidene chloride and 2-chlorobutadiene into mutagens. In the plate incorporation assay, 1,4-dichlorobutene-2 was mutagenic per se, and addition of microsomal fractions from human or mouse liver enhanced the mutagenicity; a synthetic putative metabolite, 1,4-dichloro-2,3-epoxybutane was less mutagenic than the parent olefin in strain TA100. Treatment of rats with phenobarbital or 3-methylcholanthrene caused an up to 2-fold increase in the liver microsome-mediated mutagenicities of vinyl chloride and vinylidene chloride in S. typhimurium TA1530; while treatment with pregnenolone-16α-carbonitrile, aminoacetonitrile or disulfiram decreased the mutagenic effects. Vinyl chloride, and probably vinyl bromide, were shown to be epoxidized by mouse-liver microsomes; volatile alkylating metabolites were trapped by reaction with excess 4-(4-nitrobenzyl)pyridine and analysed spectrally. 2-Chlorobutadiene also yielded an alkylating intermediate, but 1,1-difluoroethylene, 1,1-dichloroethyleneand 1,1,2-trichloroethylene did not. 2-Chloro- and 1-chlorobutadiene, 3,4-dichlorobutene-1, 1,4-dichlorobutene-2 and its 2,3-epoxy derivative showed alkylating activity with 4-(4-nitrobenzyl)pyridine, which was not related quantitatively to mutagenic activity in S. typhimurium TA100 in the absence of a metabolic activation system. These data support the hypothesis that an oxidation of the double bond in certain halo-olefins, which is dependent on microsomal mono-oxygenases is a common pathway in the formation of biologically reactive intermediates. The relevance of the metabolites formed during such oxidative processes to the mutagenic, toxic and carcinogenic activities in vivo of some of the parent compounds is discussed.

Zusammenfassung

Die mutagene Wirkung einer Reihe halogenierter Kohlenwasserstoffe wurde in Gegenwart einer postmitochondrialen Mäuseleberfraktion in zwei Stämmen von S. typhimurium gemessen. Wenn die Bakterien den gasförmigen Testsubstanzen ausgesetzt wurden, war die Mutagenität in folgender Reihenfolge: 3,4-Dichlorbuten-1 > 1-Chlorbutadien (technischer Reinheitsgrad) > 2-Chlorbutadien > Vinylbromid > Vinylidenchlorid > Vinylchlorid. 1,1,2-Trichloräthylen und 1,1-Difluoräthylen zeigten schwachen, Tetrachloräthylen und Vinylacetat keinen mutagenen Effekt. Gewebefraktionen von Menschenleber konnten Vinylchlorid, Vinylbromid, Vinylidenchlorid und 2-Chlorbutadien in mutagene Metabolite überführen. Im konventionellen Plattentest zeigte 1,4-Dichlorbuten-1 eine direkte mutagene Wirkung, die durch Zusatz von mikrosomalen Leberfraktionen von Menschen oder von der Maus erhöht wurde. Der vermutete reaktive Metabolit 1,4-Dichlor-2,3-Epoxybutan wurde synthetisiert, erwies sich aber im Stamm TA100 als ein schwächeres Mutagen als die Muttersubstanz. Die Vorbehandlung von Ratten mit Phenobarbital oder 3-Methylcholanthren verdoppelte die mikrosomenabhängige Mutagenität von Vinylchlorid und Vinylidenchlorid in S. typhimurium TA1530, Pregnenolon-16α-Carbonitril, Aminoacetonitril oder Disulfiram dagegen verminderten die mutagene Wirkung. Eine Epoxidierung von Vinylchlorid und wahrscheinlich Vinylbromid durch Mäuselebermikrosomen wurde durch die Bildung und Abfangen von flüchtigen, alkylierenden Metaboliten mit 4-(4-Nitrobenzyl)pyridin sowie spektralen Untersuchungen nachgewiesen; 2-Chlorbutadien bildete ebenfalls eine alkylierende Zwischenstufe, die in ähnlichen Experimenten mit 1,1-Difluoräthylen, 1,1-Dichloräthylen und 1,1,2-Trichloräthylen nicht nachgewiesen werden konnte. 2-Chlor- und 1-Chlorbutadien, 3,4-Dichlorbuten-1,1,4-Dichlorbuten-2 und sein 2,3-Epoxid zeigten alkylierende Wirkung in Gegenwart von 4-(4-Nitrobenzyl)pyridin, die sich quantitativ nicht mit der mutagenen Aktivität in S. typhimurium TA100 in Abwesenheit metabolischer Aktivierung korrelieren ließ. Die Ergebnisse zeigen einen gemeinsamen Bildungsweg in halogenierten Olefinen auf, der über eine mikrosomale Oxidation der Doppelbindung zu biologisch reaktiven Zwischenstufen führt. Die Bedeutung derartig gebildeter Metabolite für die mutagene, toxische und karzinogene Wirkung der Muttersubstanzen in vivo wird zusammenfassend erörtert.

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Abbreviations

VC:

Vinyl chloride

VDC:

Vinylidene chloride

CBD:

2-Chloro-1,3-butadiene

PB:

Phenobarbital

S-9:

9000 × g tissue supernatant

NBP:

4-(4-Nitrobenzyl)pyridine

G 6-P:

Glucose 6-phosphate

NADP+ :

Nicotinamide adenine dinucleotide phosphate

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  1. International Agency for Research on Cancer, 150 Cours Albert-Thomas, F-69372, Lyon Cedex 2, France

    Helmut Bartsch, Christian Malaveille, Alain Barbin & Ghyslaine Planche

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  1. Helmut Bartsch
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  2. Christian Malaveille
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Work in part fulfillment of a thesis at the University of Lyon, France, 1977

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Bartsch, H., Malaveille, C., Barbin, A. et al. Mutagenic and alkylating metabolites of halo-ethylenes, chlorobutadienes and dichlorobutenes produced by rodent or human liver tissues. Arch. Toxicol. 41, 249–277 (1979). https://doi.org/10.1007/BF00296896

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