Extracellular

FIGURE 4-3 Coding region polymorphisms in two membrane transporters. Shown are the dopamine transporter, DAT (encoded by SLCGA3) and multidrug resistance associated protein, MRP2 (encoded by ABCC2). Coding region variants were identified in 247 ethnically diverse DNA samples (100 African Americans, 100 European Americans, 30 Asians, 10 Mexicans, and 7 Pacific Islanders). Shown in light gray are synonymous variants, and in black, nonsynonymous variants.

o Synonymous Cytosollc

FIGURE 4-3 Coding region polymorphisms in two membrane transporters. Shown are the dopamine transporter, DAT (encoded by SLCGA3) and multidrug resistance associated protein, MRP2 (encoded by ABCC2). Coding region variants were identified in 247 ethnically diverse DNA samples (100 African Americans, 100 European Americans, 30 Asians, 10 Mexicans, and 7 Pacific Islanders). Shown in light gray are synonymous variants, and in black, nonsynonymous variants.

and Crigler-Najjar syndrome are examples of inherited diseases caused by single gene defects. Crigler-Najjar syndrome is a severe genetic disorder caused by rare inactivating mutations in UGT1A1. More common and less deleterious polymorphisms in UGT1A1 are associated with modest hyperbilirubinemia and altered drug clearance. Polymorphisms in other genes are highly penetrant in subjects challenged with certain drugs; these polymorphisms thus are the causes of monogenic pharmacogenetic traits. Because they are not deleterious in the constitutive state, there is unlikely to be any selective pressure for or against these polymorphisms. Most genetic polymorphisms have a modest impact on the affected genes, are part of a large array of multigenic factors that impact drug effect, or affect genes whose products play a minor role in drug action relative to large nongenetic effects. For example, phenobarbital induction of metabolism may be such an overwhelming "environmental" effect that polymorphisms in the affected transcription factors and drug-metabolizing enzymes have relatively modest effects.

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