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GENE-ENVIRONMENT

INTERACTIONS IN DRUG METABOLISM

E. S. VESELL

Departm ent 0/Pharm acology,

The Penn sylvania State University.

College ofMe dicine,

Hershey, Pennsylvan ia 17033. USA

Relationships among genetic and environmental factors that cause large variations

among normal subjects, as weil as among patients, in rates of drug elimination are

often discussed as though such factors were ent irely separate, unrelated entities

without interaction or interdependence. However, genetic and environmental factors

that control these large variations in rates of drug elimination interact dynam ically at

mult iple levels. In fact, to ach ieve expression genetic factors often require part icipation of environmental factors; and the latter often require a genetic apparatus to

exert their effects on drug dispostion . For example, the pharmacogenetic conditions

described and listed elsewhere (Table 2; Vesell, 1978) are expressed only in the

presenc e of an environmental agent: a drug . Toxicity then develops only in those

subjects whose genetic constitutions render them sensitive. The genetic factor may be

a metabolic block that leads to drug accumulation or it may consist of a structurally

altered receptor site that fails to bind the parent drug or its metabolites in anormal

way.