Cytochrome P450 2D6.1 and cytochrome P450 2D6.10 differ in catalytic activity for multiple substrates
Yamini Ramamoorthy, Rachel F. Tyndale, Edward M. Sellers
Pharmacogenetics August 1, 2001 DOI: 10.1097/00008571-200108000-00003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro experimental study Peer reviewed |
|---|---|
| Population | Baculovirus expression system expressing CYP2D6.1 and CYP2D6.10 enzymes |
| Topics | MDMA |
| Keywords | Cyp2d6 Dextromethorphan Debrisoquine Pharmacology Cytochrome p450 Sparteine Stereochemistry Hydroxylation Quinidine Metabolism |
| Citations | 92 |
| Key findings | CYP2D6.10 shows substantially reduced intrinsic clearance and altered inhibition susceptibility for multiple substrates compared to CYP2D6.1, indicating that CYP2D6*10/*10 individuals likely require different drug doses and have altered toxicity and interaction risks. |
Abstract
CYP2D6 is involved in the metabolism of several classes of drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors and various amphetamines. CYP2D6*10 is an allelic variant, producing an enzyme with Pro34Ser and Ser486Thr amino acid substitutions. Approximately 75% of Asians possess the *10 allele. We sought to further characterize CYP2D6.10 catalytically in vitro in a baculovirus expression system using various substrates and inhibitors, in comparison to CYP2D6.1 (wild-type). Using dextromethorphan (DEX), P-methoxyamphetamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and (+/-)3,4-methylenedioxymethamphetamine (MDMA), the ratios of intrinsic clearance (Vmax/Km) of *1 to *10 were 50, 34, 22 and 123, respectively. The CYP2D6 substrates amitriptyline, and (+) and (-) methamphetamine (MAMP) are both p-hydroxylated and N-demethylated (NDM). The intrinsic clearance *1/*10 ratios were 42, 30 and 67 for the p-hydroxylation; and 60, 120 and 157 for the NDM, respectively, illustrating chemical pathway and enantiomeric selectivity for MAMP. It was apparent that (+) and (-) MAMP NDM and MDMA demethylenation were most significantly different in CYP2D6.10. Using DEX as the substrate, the ratios of Ki(*10)/Ki(*1) for inhibitors were: budipine (1.3), sparteine (1.6), debrisoquine (8.1), fluoxetine (16), norfluoxetine (30), paroxetine (14), MDMA (21) and MMDA-2 (7.1), indicating that CYP2D6.10 shows drug-specific altered susceptibility to inhibition. Taken together, these data suggest that CYP2D6*10/*10 individuals may be expected to require different drug doses; and show altered susceptibility to toxicity, interaction risk and, in the case of the amphetamines, drug dependence and toxicity compared to CYP2D6*1/*1 individuals.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 7
- MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant? Frontiers in Genetics 2012
- The Neuropsychopharmacology and Toxicology of 3,4‐methylenedioxy‐N‐ethyl‐amphetamine (MDEA) CNS Drug Reviews June 1, 2004
- Behavioral profiles in rats distinguish among "ecstasy," methamphetamine and 2,5-dimethoxy-4-iodoamphetamine: Mixed effects for "ecstasy" analogues. Behavioral Neuroscience October 1, 2010
- Cocaine, metamfetamine, and MDMA abuse: the role and clinical importance of neuroadaptation. Clinical Toxicology August 2010
- Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview Molecular Neurobiology June 1, 2009
and 2 more in the library
Cites 3
- Identification of the human cytochromes P450 involved in the oxidative metabolism of "Ecstasy"-related designer drugs. Biochemical Pharmacology June 15, 2000
- Interactions of amphetamine analogs with human liver CYP2D6. Biochemical Pharmacology June 1, 1997
- Toxicity and deaths from 3,4-methylenedioxymethamphetamine ("ecstasy"). The Lancet August 15, 1992