Teratogen metabolism: thalidomide activation is mediated by cytochrome P-450

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 shi...

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Published inToxicology and applied pharmacology Vol. 82; no. 1; p. 175
Main Authors Braun, A G, Harding, F A, Weinreb, S L
Format Journal Article
LanguageEnglish
Published United States 01.01.1986
Subjects
Amines - pharmacology
Animals
Biotransformation
Carbon Monoxide - pharmacology
Catalase - metabolism
Cytochrome P-450 Enzyme System - metabolism
Dogs
In Vitro Techniques
Isoenzymes - metabolism
Microsomes, Liver - enzymology
NADP - metabolism
Proadifen - pharmacology
Spectrophotometry
Superoxide Dismutase - metabolism
Thalidomide - metabolism
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Summary: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 degrees 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 this thalidomide metabolite is involved in the drug's teratogenic activity remains to be shown.
ISSN:0041-008X
DOI:10.1016/0041-008X(86)90449-7