Niridazole metabolism by rat embryos in vitro

Authors

  • Dr. A. G. Fantel,

    Corresponding author
    1. Department of Pediatrics, Affiliates, Child Development and Mental Retardation Center, School of Medicine, University of Washington, Seattle, Washington 98195
    • Department of Pediatrics RD-20, University of Washington, Seattle, WA 98195
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  • R. E. Person,

    1. Department of Pediatrics, Affiliates, Child Development and Mental Retardation Center, School of Medicine, University of Washington, Seattle, Washington 98195
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  • J. W. Tracy,

    1. Departments of Comparative Biosciences and Pharmacology, University of Wisconsin, Madison, Wisconsin 53706
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  • M. R. Juchau

    1. Department of Pharmacology, Affiliates, Child Development and Mental Retardation Center, School of Medicine, University of Washington, Seattle, Washington 98195
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Abstract

We report the results of studies on the reductive activation of the schistosomicidal agent, niridazole (NDZ). Intact rat embryos in vitro reduced this compound, generating a stable metabolite in the presence of 5% O2. By contrast, embryo and yolk sac homogenates or liver microsomes appeared to require anaerobiasis. Malformation incidence–specifically, axial asymmetry–showed a strong correlation with nitroreductase activity rates when the latter were modulated by oxygen tension.

Data presented here suggest that when embryos are exposed to NDZ under conditions of low oxygen in vitro, redox cycling ensues with molecular oxygen serving to oxidize early reduction products. This process continues, regenerating the parent compound until oxygen is depleted locally. The basis of this localized depletion is unknown, but inability of the immature supply system to replete oxygen or demand by precociously aerobic tissues may be involved. Once local anaerobiasis is attained, further reduction could generate toxic metabolites capable of covalently binding cellular macromolecules. Localized hypoxia represents another potential mechanism of dysmorphogenesis.

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