Differential inhibition of biphenyl hydroxylation in perfused rat liver

When Day 10 rat embryos were grown in culture containing cyclophosphamide, an hepatic microsomal fraction (S-9), and cofactors for monooxygenation, they developed characteristic malformations. When a fixed volume of CP was added to cultures the number of malformed embryos was increased and their growth decreased dependent upon the S-9 concentration. In one group of experiments S-9 was prepared from animals which had been pretreated with either phenobarbital (PB) or 3-methylcholanthrene (MCA). All embryos cultured with CP by S-9 from animals pretreated with polychlorinated biphenyls (Aroclor 1254) microliter/ml) was used. No malformations were seen under the same conditions when MCA-induced S-9 (0.25-12.5 microliter/ml) was substituted. The teratogenic activation of CP by S-9 from animals pretreated with polychlorinated biphenyls (Aroclor 1254) was inhibited in vitro by the addition of either metyrapone or carbon monoxide. Embryos which were exposed to CP (25 mg/kg) in vivo on Day 10 were indistinguishable from embryos treated in vitro. All developed characteristic defects and had significant decreases in growth parameters when compared to control litters receiving only vehicle. No histological differences were seen between embryos treated in vivo or in vitro. These data provide further evidence that the teratogenicity of CP is dependent upon one or more maternal P450 monooxygenase systems.

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The in vitro teratogenicity of cyclophosphamide in rat embryos

Greenaway

Fantel

Shepard

et al. 1982

Teratology

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Teratogenicity of chlorambucil in rat embryos in vitro

Mirkes

Greenaway

1982

Teratology

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Chlorambucil, a bifunctional alkylating agent and antitumor drug, is a potent teratogen in rodents and possibly teratogenic in humans. Unlike cyclophosphamide, a related bifunctional alkylating agent, chlorambucil is a direct-acting cytotoxic agent. However, several studies indicate that the cytotoxic potential of chlorambucil is enhanced by metabolism of the parent compound. Using day-10 rat embryos cultured in vitro, we have demonstrated that chlorambucil is a direct acting teratogen but that its teratogenicity can be enhanced by the addition of rat liver S-9 preparations to culture medium containing the drug. Our data also suggest that this enhancement is not related to cytochrome P-450 monooxygenases. This conclusion is based upon three lines of evidence. First, enhancement occurs under culture conditions which lack cofactors necessary for cytochrome P-450 monooxygenases. Second, metyrapone, a known inhibitor of cytochrome P-450, did not abolish the enhancement. Third, induction of cytochrome P-450 by two specific inducers of monoxygenase activity had no effect on the observed enhancement. We postulate that the observed enhancement of chlorambucil teratogenicity is related to the beta-oxidation of the butyric acid side chain of chlorambucil generating the more cytotoxic (teratogenic) metabolite, phenylacetic acid mustard. Finally, our data indicate that the teratogenic effects elicited by chlorambucil are indistinguishable from those elicited by cyclophosphamide.

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Effect of various metabolic inhibitors on biphenyl metabolism in isolated rat hepatocytes

Wiebkin

Parker

Fry

et al. 1979

Biochemical Pharmacology

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Differential inhibition of biphenyl hydroxylation in perfused rat liver

Cited by 7 publications

References 14 publications

The in vitro teratogenicity of cyclophosphamide in rat embryos

The in vitro teratogenicity of cyclophosphamide in rat embryos

Teratogenicity of chlorambucil in rat embryos in vitro

Effect of various metabolic inhibitors on biphenyl metabolism in isolated rat hepatocytes

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