enzymes. Phase I enzymes catalyze a conversion of the exogenous agent to a modified form, often an oxidized form. In some cases, the exogenous agent is toxic and the intermediate is not, but in other cases, the agent is nontoxic and the intermediate is toxic, an example of metabolic potentiation or activation. There probably are several hundred kinds of phase I enzymes (and genes encoding them) in mammals (including humans). The majority of them are members of the large cytochrome P450 monooxygenase family. Three or four kinds of P450 enzymes are thought to metabolize 70-80% of the prescription drugs taken by patients, and defects in phase I enzymes correlate with drug sensitivities and hazardous side effects. Phase II enzymes subsequently catalyze the conjugation of the modified intermediate to an endogenous harmless metabolite, such as a sugar or amino acid, and the conjugated form, which is usually nontoxic, is then excreted. In several well-analyzed cases, patients with high levels of phase I enzyme (hence, producing high amounts of a toxic intermediate) and low levels of phase II enzyme (hence, unable to get rid of that intermediate) were found to be particularly at risk from chemical exposures. Thus, human variants with altered levels of enzymes of one group or the other, or both, can have abnormal drug responses, as much as a 20- or 30-fold increase in drug sensitivity.

At least 60 ecogenetic or pharmacogenetic differences are now known; many are listed in Table 5-1. In this research, epidemiological methods and genomic methods are complementary, and progress in the near future seems assured. It seems likely that the fetus is at increased risk of developmental defects, because either the mother or the fetus cannot metabolize chemicals as well as others can or because they metabolize them better.

The other large area to investigate for the correlation of polymorphisms with developmental defects is that of the components of the developmental processes themselves, namely, key components of developmental processes, such as those of signal transduction pathways and genetic regulatory circuits. These components are the targets of exogenous agents that elude detoxification or are potentiated by phase I enzymes. The examples of TGFα with smoking and MSX1 with limb defects are two that have been clarified. At this time, however, there are few good examples, perhaps simply because information about developmental processes has not been available until recently. Because the developmental components are conserved across phyla and have been well described in Drosophila, C. elegans, and now the mouse, the means are available to obtain related human sequences and search for polymorphisms. This research will be further discussed in Chapters 8 and 9. The phenotypes of mouse null mutants generated by the embryonic stem-cell-(ES) knockout technology have already contributed substantially to our knowledge about how alterations in those genes and pathways impact development. This kind of research is progressing rapidly. Complete deletion of some components of a variety of pathways fundamental to development results in embryo lethality, but in other cases for which there is a gene redundancy for the component, the deletion of the component leads to mice born with developmental



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