Contribution of CYP3A5 to hepatic and renal ifosfamide N-dechloroethylation.
نویسندگان
چکیده
Ifosfamide nephrotoxicity is attributed to the formation of a toxic metabolite, chloroacetaldehyde, via N-dechloroethylation, a reaction that is purportedly catalyzed by CYP3A and CYP2B6. Because allelic variants of CYP3A5 are associated with polymorphic expression of microsomal CYP3A5 in human liver and kidneys, we hypothesized that ifosfamide N-dechloroethylation depends on CYP3A5 genotype. We compared ifosfamide N-dechloroethylation activity in cDNA-expressed CYP3A4 and CYP3A5. Ifosfamide N-dechloroethylation was also assessed in liver (N = 20) and kidney (N = 21) microsomes from human donors with different CYP3A5 genotypes. Ifosfamide N-dechloroethylation was catalyzed by recombinant CYP3A5 at a rate comparable with recombinant CYP3A4. In human liver microsomes matched for CYP3A4 protein content, N-dechloroethylation was more than 2-fold higher in that from donors carrying CYP3A5*1 allele that express CYP3A5 relative to that from donors homozygous for the mutant CYP3A5*3. Correlation analysis revealed that ifosfamide N-dechloroethylation was significantly associated with CYP3A4 and CYP3A5 protein concentration but not with age, sex, or CYP2B6 protein concentration. In hepatic microsomes not expressing CYP3A5 protein, ifosfamide N-dechloroethylation was inhibited 53 to 61% and 0 to 3% by monoclonal antibodies specific for CYP3A4/5 or CYP2B6, respectively. Ifosfamide N-dechloroethylation was not detected in renal microsomes obtained from CYP3A5*3/*3 donors. In contrast, it was readily measurable in microsomes isolated from four kidneys of CYP3A5*1 carriers, which was almost completely inhibited by the CYP3A inhibitor ketoconazole. CYP2B6 protein could not be detected in this panel of human renal microsomes. In conclusion, CYP3A5*1 genotype is associated with higher rates of ifosfamide N-dechloroethylation in human liver and kidneys.
منابع مشابه
DMD # 2279 1 Contribution of CYP 3 A 5 to hepatic and renal ifosfamide N - dechloroethylation
متن کامل
Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide.
The anticancer alkylating agents cyclophosphamide (CPA) and ifosfamide (IFA) are prodrugs that undergo extensive P450-catalyzed metabolism to yield both active (4-hydroxylated) and therapeutically inactive but neurotoxic (N-dechloroethylated) metabolites. Whereas the human liver microsomal P450 catalysts of CPA and IFA 4-hydroxylation are well characterized, the P450 enzyme catalysts of the alt...
متن کاملDmd063628 1084..1090
The hydroxylation and N-dechloroethylation of deuterated ifosfamide (d4IFO) and ifosfamide (IFO) by several human P450s have been determined and compared. d4IFO was synthesized with deuterium at the alpha and alpha9 carbons to decrease the rate of N-dechloroethylation and thereby enhance hydroxylation of the drug at the 49 position. The purpose was to decrease the toxic and increase the efficac...
متن کاملHydroxylation and N-dechloroethylation of Ifosfamide and deuterated Ifosfamide by the human cytochrome p450s and their commonly occurring polymorphisms.
The hydroxylation and N-dechloroethylation of deuterated ifosfamide (d4IFO) and ifosfamide (IFO) by several human P450s have been determined and compared. d4IFO was synthesized with deuterium at the alpha and alpha' carbons to decrease the rate of N-dechloroethylation and thereby enhance hydroxylation of the drug at the 4' position. The purpose was to decrease the toxic and increase the efficac...
متن کاملCYP3A5 genotype does not influence everolimus in vitro metabolism and clinical pharmacokinetics in renal transplant recipients.
BACKGROUND CYP3A5 genotyping might be useful to guide tacrolimus and sirolimus dosing. The aim of this study was to assess the influence of CYP3A5 polymorphism on everolimus metabolism and pharmacokinetics. METHODS We investigated the effect of CYP3A5 6986A>G polymorphism (CYP3A5*1/*3 alleles) on the pharmacokinetics of everolimus in 28 renal transplant patients and on its in vitro hepatic me...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Drug metabolism and disposition: the biological fate of chemicals
دوره 33 7 شماره
صفحات -
تاریخ انتشار 2005