Tamoxifen has been used as adjuvant hormonal therapy for estrogen receptor positive breast cancer for over 30 years and is also widely used for the treatment of metastatic breast cancer. Tamoxifen is metabolized to its more active form by cytochrome P450 2D6 (CYP2D6); decreases in CYP2D6 activity, either by inactivating polymorphisms or drug interactions, can reduce concentrations of tamoxifen'...

We analyzed cytochrome P450 2D6 polymorphism by determining phenotype as the metabolic ratio between dextromethorphan and its main metabolite, dextrorphan. We studied 18 men and 22 women in whom mean age was 54.6+/-11.9 years. In 9 patients metabolic ratio was determined before antiarrhythmic treatment and again during treatment, with a mean increase of 0.13+/-0.15 (P=.03). We found 19 poor met...

Tamoxifen remains a cornerstone of treatment for patients with oestrogen-receptor-positive breast cancer. Tamoxifen efficacy depends on the biotransformation, predominantly via the cytochrome P450 2D6 (CYP2D6) isoform, to the active metabolite endoxifen. Both genetic and environmental (drug-induced) factors may alter CYP2D6 enzyme activity directly affecting the concentrations of active tamoxif...

QUESTION Recently a newborn died from morphine poisoning when his mother used codeine while breastfeeding. Many patients receive codeine for postlabour pain. Is it safe to prescribe codeine for nursing mothers? ANSWER When a mother is an ultrarapid metabolizer of cytochrome P450 2D6, she produces much more morphine when taking codeine than most people do. In this situation, newborns might be ...

The cytochrome P450 2D6 (CYP2D6) gene is perhaps the most well characterized gene involved in drug metabolism and is known to have both gene duplication and deletion variants that are inheritable and stable. In a set of over 30,000 deidentified clinical samples we found that 12.6% of all patients tested had zero, one, or three or more copies of the CYP2D6 gene. On the basis of the combined freq...

The stereoselective binding of R- and S-propranolol to the metabolic enzyme cytochrome P450 2D6 and its mutant F483A was studied using various computational approaches. Previously reported free-energy differences from Hamiltonian replica exchange simulations, combined with thermodynamic integration, are compared to the one-step perturbation approach, combined with local-elevation enhanced sampl...

We report the identification of a novel and defective variant of the gene encoding cytochrome P450 2D6 (CYP2D6). This novel variant is a subtype of CYP2D6*6 that was undetected by a commercially available 5' exonuclease-based assay. Because the novel variant was found in only one of 609 individuals, it represents a rare subtype of CYP2D6*6 that may be restricted to a single family or a subpopul...

Highly selective cytochrome P450 CYP2J2 (CYP2J2) inhibitors suitable for reaction phenotyping are currently not available. (7S)-(+)-(4-Nitro-phenyl)-acrylic acid, 8,8-dimethyl-2-oxo-6,7-dihydro-2H,8H-pyrano[3,2-g]chromen-7-yl-ester (LKY-047), a decursin derivative, was synthesized, and its inhibitor potencies toward CYP2J2 as well as other cytochrome P450 (P450) enzymes in human liver microsome...

Cytochrome P450 2D6 (CYP2D6), which has a large number of genetic polymorphisms, is involved in the metabolism of a wide range of substrates. Dextromethorphan (DM) is a well-known probe drug for CYP2D6 and metabolic ratio (MR) is often used to measure the enzyme activity in vivo. Using the literature values of DM MR, we estimated the inter-individual variability of CYP2D6 hepatic intrinsic clea...

The tobacco specific carcinogen N'-nitrosonornicotine (NNN), is believed to be a causative agent for esophageal cancer in smokers. NNN requires metabolic activation to exert its carcinogenic potential. Metabolism occurs through cytochrome P450 (P450) catalyzed 2'- and 5'-hydroxylation, which generates unstable metabolites that decompose to 4-hydroxy-1-(3-pyridyl)-1-butanone ('keto alcohol') and...