Thalidomide has been shown to cause limb reduction defects in rabbits with much greater potency than in rats, possibly due to inherent biochemical differences between the two species. Whole embryo culture was used to make direct comparisons between thalidomide-sensitive New Zealand White rabbits and thalidomide-resistant Sprague-Dawley rats, focusing on the possible roles of glutathione (GSH) and cysteine in mechanisms of thalidomide teratogenicity. Conceptuses were treated by adding thalidomide (0, 5, 15, and 30 microM) directly to the culture media containing conceptuses of similar gestational stages. Embryos and visceral yolk sacs (VYS) were measured for changes in GSH and cysteine content using HPLC after 24 h of exposure in vitro. Thalidomide-induced (15 and 30 microM) depletion of VYS GSH occurred only in the rabbit, where GSH concentrations (pmol/microg protein) fell significantly to about 50% of control. Rat VYS did not show a significant GSH depletion at any thalidomide concentration tested. Comparison between species showed that the control rabbit VYS contained 35% less GSH than the control rat VYS. Control rat embryos and control rabbit embryos contained similar concentrations of GSH, but thalidomide treatment preferentially depleted GSH in the rabbit at lower thalidomide concentrations (5 micro/M). Cysteine concentrations were not significantly altered from control in the embryo or VYS of either species when treated with thalidomide. However, although control cysteine concentrations did not differ significantly between rat and rabbit VYS, control cysteine levels in rabbit embryos were 65% lower than those in control rat embryos. Rabbit conceptuses displayed lower species-specific GSH and cysteine levels and a greater propensity for thalidomide-induced GSH depletion than in rat conceptuses, consistent with the greater sensitivity of the rabbit to thalidomide teratogenicity. These thalidomide-induced and inherent species differences implicate a possible role for GSH and redox status in the mechanisms of thalidomide teratogenicity.

Animals↗

PubMedDate not supplied

Accumulation of chlorpropamide caused by dicoumarol.

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Aged↗

PubMedDate not supplied

Effect of diphenylhydantoin on the metabolism of dicoumarol in man.

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Carbon Isotopes↗

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Audiological and temporal bone findings in myxedema.

Fifteen patients with confirmed myxedema at a median age of 48 years (range 32 to 60 years) were referred for audiological evaluation before and after treatment with levothyroxine. The median interval between the pretreatment and posttreatment investigations was 18 months (range 9 to 27 months). In addition, 13 patients at a median age of 78 years (range 64 to 95 years) were audiologically reexamined after long-standing levothyroxine treatment. The observation period upon treatment with levothyroxine was 40 months (range 32 to 46 months). No improvement in hearing sensitivity could be demonstrated either in the younger patients or in the elderly. When compared to an age- and sex-matched unscreened population, the myxedematous patients did not demonstrate any different degree of hearing loss. Histological investigation of the temporal bones from an 83-year-old woman with myxedema, however, showed no morphological changes or deposition of glycosaminoglycans, changes which are compatible with true age-related hearing loss. It is concluded that no association exists between myxedema and hearing impairment and that no morphological or structural changes due to myxedema can be demonstrated in the temporal bones.

Adult↗