Role Of Metabolic Activation

There is clear evidence from many different sources that the metabolism of compounds may be involved in their teratogenic effects, as will be seen in the final chapter in the discussion of thalidomide and diphenylhydantoin teratogenicity. The embryo and foetus of some species clearly have metabolic activity towards foreign compounds which may be inducible by other foreign compounds. Thus, foetal liver from primates has a more well-developed metabolic system for xenobiotics than does that from rodents and rabbits for example. This may be due to the late development of the smooth endoplasmic reticulum and therefore of cytochrome(s) P-450 in the latter species. The use of metabolic inducers and inhibitors in vivo and the use of metabolizing systems with embryo or limb bud

Thalidomide Rodent Rabbit

FIGURE 6.19 Metabolism of diethylstilboestrol via an epoxide intermediate. This potentially reactive intermediate may show an affinity for the oestradiol receptor and thereby accumulate in oestrogen target organs. This may facilitate reaction with DNA in these organs. From Metzler andMcLachlan (1979) Archs. Toxicol, Suppl. 2, 275.

FIGURE 6.19 Metabolism of diethylstilboestrol via an epoxide intermediate. This potentially reactive intermediate may show an affinity for the oestradiol receptor and thereby accumulate in oestrogen target organs. This may facilitate reaction with DNA in these organs. From Metzler andMcLachlan (1979) Archs. Toxicol, Suppl. 2, 275.

culture in vitro, have all indicated that for some teratogens, metabolism is involved. Metabolic activation in the maternal organism or in the embryo itself may both occur and have different roles in the eventual toxicity.

A good example of a compound which is a teratogen and which requires metabolic activation is the anticancer drug cyclophosphamide, which has been studied extensively both in vivo and in vitro. However, just as with other toxic effects, either the parent drug or a metabolite may be responsible for embryotoxicity, but it is often difficult to predict which, without substantial metabolic and biochemical data being available.

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