Cytochrome P450 2D6.1 and cytochrome P450 2D6.10 differ in catalytic activity for multiple substrates
Pharmacogenetics August 1, 2001 Yamini Ramamoorthy, Rachel F. Tyndale, Edward M. Sellers 92 citations
The CYP2D6 enzyme metabolizes many drugs, including antidepressants and amphetamines. A common variant, CYP2D6*10, found in about 75% of Asians, has Pro34Ser and Ser486Thr substitutions. In vitro tests using a baculovirus system showed that CYP2D6.10 has much lower intrinsic clearance than the wild-type CYP2D6.1 for several substrates: for dextromethorphan, the clearance ratio was 50; for MDMA, 123; for p-hydroxylation of methamphetamine, ratios ranged from 30 to 67; for N-demethylation, from 60 to 157, showing pathway and enantiomer selectivity. Inhibition susceptibility also varied: for debrisoquine, the Ki ratio was 8.1; for fluoxetine, 16; for norfluoxetine, 30. These findings suggest that individuals with CYP2D6*10/*10 may need different drug doses and have altered risks for toxicity, interactions, and amphetamine dependence compared to those with CYP2D6*1/*1.