Q172H Replacement Overcomes Effects on the Metabolism of Cyclophosphamide and Efavirenz Caused by CYP2B6 Variant with Arg262
- 5 August 2011
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Drug Metabolism and Disposition
- Vol. 39 (11), 2045-2048
- https://doi.org/10.1124/dmd.111.039586
Abstract
There are a number of reports indicating that CYP2B6*6 (c.516G>T and c.785A>G) is responsible for decreased clearance of efavirenz (EFV), although increased disposition of cyclophosphamide (CPA) in individuals with this polymorphism was observed. Thus, we hypothesized that the effects of the two single nucleotide polymorphisms (SNPs) of CYP2B6*6 on the metabolism of drugs might be considerably different between these two agents. To clarify this possibility, we expressed two major variants of this enzyme, CYP2B6.6 (Q172H and K262R) and CYP2B6.4 (K262R), and investigated metabolic activities of these variants toward EFV and CPA. Kinetic analyses clearly indicated that CYP2B6.4 possessed enhanced metabolic activity toward EFV compared with that of the wild-type enzyme (CYP2B6.1), whereas CPA was metabolized less efficiently by CYP2B6.4 than by CYP2B6.1. On the other hand, CYP2B6.6 showed a completely opposite character, suggesting that Q172H gives inverse effects on metabolic activities of CYP2B6 affected by K262R. Although it is recognized that effects of amino acid change in cytochrome P450 on the metabolic activity depend on substrates, this study revealed SNPs giving an opposite effect on the metabolism of two clinically important drugs currently used. Furthermore, this study provides the first evidence that Q172H can reverse the direction of the effect caused by K262R in CYP2B6 on the metabolism of certain drugs.Keywords
This publication has 20 references indexed in Scilit:
- Aberrant Splicing Caused by Single Nucleotide Polymorphism c.516G>T [Q172H], a Marker of CYP2B6*6, Is Responsible for Decreased Expression and Activity of CYP2B6 in LiverJournal of Pharmacology and Experimental Therapeutics, 2008
- Genetic polymorphisms of CYP2B6 affect the pharmacokinetics/pharmacodynamics of cyclophosphamide in Japanese cancer patientsPharmacogenetics and Genomics, 2007
- Metabolism of Efavirenz and 8-Hydroxyefavirenz by P450 2B6 Leads to Inactivation by Two Distinct MechanismsJournal of Pharmacology and Experimental Therapeutics, 2006
- Influence of 516G>T Polymorphisms at the Gene Encoding the CYP450-2B6 Isoenzyme on Efavirenz Plasma Concentrations in HIV-Infected SubjectsClinical Infectious Diseases, 2005
- Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimensBiochemical and Biophysical Research Communications, 2004
- Hepatic CYP2B6 Expression: Gender and Ethnic Differences and Relationship toCYP2B6Genotype and CAR (Constitutive Androstane Receptor) ExpressionJournal of Pharmacology and Experimental Therapeutics, 2003
- The Cytochrome P450 2B6 (CYP2B6) Is the Main Catalyst of Efavirenz Primary and Secondary Metabolism: Implication for HIV/AIDS Therapy and Utility of Efavirenz as a Substrate Marker of CYP2B6 Catalytic ActivityJournal of Pharmacology and Experimental Therapeutics, 2003
- Role of polymorphic human CYP2B6 in cyclophosphamide bioactivationThe Pharmacogenomics Journal, 2003
- A Single Nucleotide Polymorphism of CYP2B6 Found in Japanese Enhances Catalytic Activity by AutoactivationBiochemical and Biophysical Research Communications, 2001
- Primer-Directed Enzymatic Amplification of DNA with a Thermostable DNA PolymeraseScience, 1988