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TERATOGEN METABOLISM: THALIDOMIDE ACTIVATION IS MEDIATED BY CYTOCHROME P-450
Citation:
Braun, A., F. Harding, AND S. Weinreb. TERATOGEN METABOLISM: THALIDOMIDE ACTIVATION IS MEDIATED BY CYTOCHROME P-450. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-86/089 (NTIS PB86208527), 1986.
Description:
A metabolite of thalidomide generated by hepatic microsomes inhibited the attachment of tumor cells to concanavalin A-coated polyethylene. Evidence that metabolite formation is mediated by microsomal cytochrome P-450 is presented. Microsomes incubated with thalidomide underwent a type I spectral shift. Metabolite formation was reduced or eliminated by carbon monoxide, SKF-525A, metyrapone, and N-octylamine. Superoxide dismutase treatment had no effect. Metabolite formation required microsomes and NADPH and was dependent on the length of 37 C incubation. The metabolite could be isolated by successive hexane and chloroform extractions. It is likely the inhibitory thalidomide metabolite was generated by a minor cytochrome P-450 species. Whether the thalidomide metabolite is involved in the drug's teratogenic activity remains to be shown.