[Cyclophosphamide and CYP2B6].
Members of the hepatic cytochrome p450 superfamily(CYP)play an important role in the metabolism of many therapeutic drugs. There is a marked individual variability in the CYP-mediated drug metabolism. One of the main factors of the CYP activities is a polymorphism of the CYP genes. Polymorphisms of the CYP genes contribute to the variation in the drug-metabolic rate. The polymorphic nature of the CYP genes affects the individual drug response and adverse reactions. Cyclophosphamide(CPA)exerts its effect after biotransformation to 4-hydroxy-CPA by hepatic CYP. Several CYPs have been reported to mediate this reaction. Especially CYP2B6 is thought to be the key enzyme in the CPA metabolism. CYP2B6 is highly polymorphic, and it has been reported that the genetic backgrounds of CYP2B6 in Japanese and Caucasians are different. CYP2B6*6, which is a relatively common allele in the Japanese population, affects the gene expression and activities of CYP2B6 in vitro. The homozygote of CYP2B6*6 patients with malignant lymphoma and breast cancer treated with CPA showed higher clearance and shorter half-life of plasma CPA. In addition, homozygous CYP2B6*5 patients with proliferative lupus nephritis had a significantly higher probability of reaching end-stage renal disease by pulse CPA treatment. Other gene polymorphisms of CYP2B6 also affect the CPA metabolism in vitro. However, the current knowledge of CYP2B6 polymorphism is not sufficient to predict its efficacy and safety for the individual patient in CPA therapy. Further studies are needed for clinical use.
Torimoto
Yoshihiro
Y
Oncology Center, Asahikawa Medical College Hospital, Hokkaido, Japan.
Kohgo
Yutaka
Y
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D003520:Cyclophosphamide / Q000378:metabolism*; D065702:Cytochrome P-450 CYP2B6; D006801:Humans; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics
D003520:Cyclophosphamide; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating