Ifosfamide Metabolite Chloroacetaldehyde Causes Renal Dysfunction in vivo

Springate, James E.

doi:10.1002/(sici)1099-1263(199701)17:1<75::aid-jat397>3.3.co;2-3

Cited by 30 publications

(45 citation statements)

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“…It has been shown that only metabolites of IFO are toxic to the kidney, whereas the prodrug is not (10). IFO must be oxidized by cytochrome 3A5 (CYP3A5) and CYP2B6 oxidase to acquire an antineoplastic activity (11,12).…”

Section: Introductionsupporting

confidence: 90%

Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

et al. 2006

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The efficacy of ifosfamide (IFO), an antineoplastic drug, is severely limited by a high incidence of nephrotoxicity of unknown etiology. We hypothesized that inhibition of complex I (C-I) by chloroacetaldehyde (CAA), a metabolite of IFO, is the chief cause of nephrotoxicity, and that agmatine (AGM), which we found to augment mitochondrial oxidative phosphorylation and B-oxidation, would prevent nephrotoxicity. Our model system was isolated mitochondria obtained from the kidney cortex of rats treated with IFO or IFO + AGM.

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Section: Introductionsupporting

confidence: 90%

Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

et al. 2006

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“…Both acrolein and chloroacetaldehyde cause toxicity in LLC-PK1 cells (Mohrmann et al, 1992(Mohrmann et al, , 1993; however, acrolein does not impair the function of isolated perfused rat kidneys or after long-term exposure in animal models (Parent et al, 1992;Zamlauski-Tucker et al, 1994). Chloroacetaldehyde has consistently shown a concentration-dependent cytotoxic effect in several in vitro models (i.e., porcine or rabbit cultured renal tubules and isolated perfused rat kidneys) with a minimum toxic concentration that ranges from 12.5 to 64 M (Mohrmann et al, 1993;Springate, 1997;Springate et al, 1999). In cultured primary human proximal tubules cells, the minimum chloroacetaldehyde concentration for toxicity was reported to be 500 M, which is well above the observed peak plasma concentrations (i.e., 0.5-109 M) in patients receiving standard doses of ifosfamide (Goren et al, 1986;Kurowski and Wagner, 1993;Dubourg et al, 2001).…”

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confidence: 67%

CONTRIBUTION OF CYP3A5 TO HEPATIC AND RENAL IFOSFAMIDEN-DECHLOROETHYLATION

et al. 2005

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ABSTRACT: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 Ndechloroethylation 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.

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“…IF mustard, which is produced by ring hydroxylation pathway, is the pharmacological active metabolite, whereas chloroacetaldehyde, which is produced from chlorethyl side oxidation, is largely believed to be responsible for the nephrotoxic effects of IF. 9 Many recent studies considered statins as the potential therapeutic agent for a targeted conservative treatment of female gonadal function, fertility 10 endometriosis in humans 11 and reduced mortality among women affected by endometrial/ovarian malignancies. 12 Whereas Andrisani et al 13 found Astaxanthin (Asta), a photo-protective red pigment of the carotenoid family, utilized to decrease male idiopathic infertility.…”

Section: Introductionmentioning

confidence: 99%

The effects ofN-acetyl-l-cysteine on the female reproductive performance and nephrotoxicity in rats

Helal

2016

Renal Failure

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This study was designed to investigate whether the treatment with the N-acetyl-L-cysteine prior to the administration of chemotherapy drug would prevent from nephrotoxicity and the loss of reproductive performance induced from chemotherapy treatment. Female rats were divided into five equal groups of six each: 1/control group; 2/rats i.p administered saline solution; 3/rats i.p administered holoxan (50 mg/kg b.wt); 4/rats i.p administered N-acetyl-L-cysteine (160 mg/kg b.wt); 5/rats i.p administered holoxan and N-acetyl-L-cysteine at the same doses. After medications, females rats were allowed to mate with males and the pregnant rats were sacrificed on day 18 of gestation. Premating treatment with holoxan showed reduction (p50.05) in reproductive performance. Whereas administration of N-acetyl-L-cysteine prior to treatment with holoxan and then concurrently with it modulated significantly fertility index, progesterone level, decreasing postimplantation loss, resorbed fetuses and improved fetal growth. Additionally, holoxan elevated the renal nicotinamide dinucleotide phosphate (NADPH) oxidase activity, oxidative stress, renal functions and caused histological changes in renal tissue. N-Acetyl-L-cysteine treatment reduced (p50.05) renal tissue NADPH oxidase, nitric oxide, malondialdehyde and improved super oxide dismutase (SOD) depletion, elevated levels phosphate, total protein and calcium as well as prevented renal histological damages. N-Acetyl-L-cysteine can confer protection against nitrosative and oxidative stresses in renal tissue induced by holoxan by suppressing NADPH oxidase activation, malondialdehyde, nitric oxide and restoring SOD activity which led to the reduction of reactive oxygen species production and subsequently might effectively improve the gonadal hormone disturbance and reproductive functions. ARTICLE HISTORY

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Ifosfamide Metabolite Chloroacetaldehyde Causes Renal Dysfunction in vivo

Cited by 30 publications

References 0 publications

Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

CONTRIBUTION OF CYP3A5 TO HEPATIC AND RENAL IFOSFAMIDEN-DECHLOROETHYLATION

The effects ofN-acetyl-l-cysteine on the female reproductive performance and nephrotoxicity in rats

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