Change in response due to altered enzyme induction


Aryl hydrocarbon receptor (AHR) polymorphism (CYP1A1 and CYP1A2 inducibility polymorphism) correlated with cancer, immunosuppression, birth defects, chloracne, porphyria, and, possibly, eye toxicity and ovarian toxicity

Abnormal metal distribution

Iron (hemochromatosis, HFE), copper (Wilson disease, Menkes disease), and, possibly, lead, cadmium, and others

Disorders of unknown etiology (known to run in families)

Corticosteroid (eye drops)-induced glaucoma

Halothane-induced hepatitis

Chloramphenicol-induced aplastic anemia

Aminoglycoside antibiotic-induced deafness

Beryllium-induced lung disease

Hepatitis B vaccine resistance

Susceptibility to human immunodeficiency virus infection (polymorphism of CCR5 coreceptors)

Long-QT syndrome

Retinoic acid resistance and acute promyelocytic leukemia

Thombophilia (activated protein C resistance)

Lactose intolerance

Fructose intolerance

Beeturia; red urine after eating beets

Malodorous urine after eating asparagus

Reproductive disadvantage in F508 cystic fibrosis heterozygotes who smoke cigarettes (CFTR)

High risk of cerebral vein thrombosis in defective prothrombin (F2) heterozygotes

High risk of cerebral vein thrombosis in users of oral contraceptives

aModified from Nebert (1999). See also refs. 11 and 18 of Nebert (1999). All of these are pharmacogenetic or ecogenetic in the sense that health risk correlates not only with the polymorphic state of the individual, but also exposure of that individual to a particular chemical (drug or environmental agent). Many of these are searchable in the online Mendelian Inheritance in Man (OMIM) database at Not all of these are correlated with developmental defects.

defects resembling human defects (see examples in Chapter 6). The work on key developmental components in animals can greatly benefit the search for human variants of developmental components.

The final step, though, will be to evaluate how specific toxicants interact with those altered pathways to produce abnormal development. Relevant susceptibility genes of development can then be examined in human populations, and interactions between alleles of those genes and toxicant exposures can be identified. Whether allelic variants of genes controlling development, such as those encoding components of the major signal transduction pathways, will be more important, as important, or less important than those controlling DMEs remains to be determined and should be given high priority for future research.

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