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Vol. 31, Issue 4, 398-403, April 2003
Division of Environmental Chemistry, National Institute of Health
Sciences, Tokyo, Japan
Cytochrome P450 (P450) 2B6 is a hepatic enzyme of potential
importance for the metabolism of clinically used drugs and
environmental or abused toxicants. Genetic polymorphisms of
CYP2B6 (CYP2B6*2, CYP2B6*3, CYP2B6*4,
CYP2B6*5, CYP2B6*6 and
CYP2B6*7; wild-type, CYP2B6*1) were found
previously in white and Japanese populations. In the present
study, the goal was to investigate the effects of amino acid
substitutions on CYP2B6 function. Wild-type (CYP2B6.1) and all of the
known variants of CYP2B6 (CYP2B6.2, CYP2B6.3, CYP2B6.4, CYP2B6.5,
CYP2B6.6, and CYP2B6.7) were transiently expressed in COS-1 cells, and
their 7-ethoxy-4-trifluoromethylcoumarin O-deethylation activities were determined. The levels of the variant CYP2B6 proteins were relatively low compared with that of CYP2B6.1, although the differences were not significant. The activities of
7-ethoxy-4-trifluoromethylcoumarin O-deethylation on
the basis of the CYP2B6 protein level at low (0.5 µM) and high (50 µM) substrate concentrations varied among wild-type and variant
CYP2B6 proteins. All CYP2B6 enzymes showed typical Michaelis-Menten
kinetics. The Km value of CYP2B6.6 was significantly higher than that of CYP2B6.1. Those CYP2B6 variants having a Lys262Arg substitution (CYP2B6.4, CYP2B6.6, and CYP2B6.7) showed increased values for Vmax and
Vmax/Km, whereas
the kinetic parameters of CYP2B6.2 and CYP2B6.3 were not affected by
the corresponding amino acid substitution. These results may mean that
Lys262 in combination with other amino acid residues such as Gln172 and Arg487 is associated with the CYP2B6 function and that the genetic polymorphism of CYP2B6 leads to interindividual
differences in xenobiotic metabolism.
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