Teratogen metabolism: spontaneous decay products of thalidomide and thalidomide analogues are not bioactivated by liver microsomes.
Thalidomide and two analogues, EM87 and EM12, inhibited the attachment of tumor cells to concanavalin A-coated surfaces only if the drugs were first incubated with hepatic microsomes and cofactors. Most agents that inhibit attachment are demonstrated teratogens. Thalidomide undergoes spontaneous hydrolysis to at least 12 products in saline buffered to a pH of greater than 7. These hydrolysis products did not inhibit attachment nor could they be activated to inhibitory products with hepatic microsomes. Similarly EM12 and EM 87 hydrolysis products were neither inhibitory nor substrates for activation. If the three drugs were incubated in buffered saline, there was a progressive decline in their ability to act as substrates for activation to an inhibitory product. It was possible to remove microsomes from the incubation mixture following drug activation by centrifugation. This microsome-free mixture inhibited cell attachment. When mouse ovarian tumor (MOT) cells were added to the microsome-free mixture, attachment was inhibited. However, if the activated drugs were incubated in saline, there was a progressive decline in their ability to inhibit attachment. Decay rates differed for the three compounds. At a pH of 7.4, thalidomide, EM87, and EM12 required 3 h, 1h and 6h, respectively, to decay to control levels. These relative rates of decay are consistent with the relative teratogenicity of the three drugs.
Braun
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Weinreb
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D000818:Animals; D001711:Biotransformation; D002460:Cell Line; D004355:Drug Stability; D005260:Female; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D051379:Mice; D008809:Mice, Inbred C3H; D008862:Microsomes, Liver / Q000378:metabolism*; D010051:Ovarian Neoplasms; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D013792:Thalidomide