Abstract：
:Mechanisms leading to ifosfamide (IF)-induced renal damage have not been fully elucidated. Recent work suggests that localized renal tubular metabolism of IF and the production of the nephrotoxic chloroacetaldehyde may lead to nephrotoxicity. Presently no pharmacological method to reduce IF nephrotoxicity has been identified. The objectives of this study were to establish a tubule cell model for IF nephrotoxicity, to verify whether renal proximal tubular cells have the necessary cytochrome P450 (CYP) enzymes to oxidize IF, and whether they can metabolize IF to chloroacetaldehyde. CYP3A, and 2B mRNA and protein were identified in LLCPK-1 cells. The cells metabolized the R- and S-IF enantiomers to their respective 2- and 3-dechloroethylifosfamide metabolites, by-products of chloroacetaldehyde formation. Metabolite production was both time and concentration-dependent. IF did not affect cell viability. In contrast, glutathione-depleted cells showed time and dose-dependent damage. The presence of the relevant CYP enzymes in renal tubular cells along with their ability to metabolize IF to its 2- and 3-dechloroethylifosfamide metabolites suggests that nephrotoxic damage may result from the localized production of chloroacetaldehyde. Glutathione is a major defence mechanism against IF toxicity, thus pharmacological methods for replenishing intracellular glutathione may be effective in modulating IF-induced nephrotoxicity.
journal_name
Can J Physiol Pharmacoljournal_title
Canadian journal of physiology and pharmacologyauthors
Aleksa K,Halachmi N,Ito S,Koren Gdoi
10.1139/y05-036subject
Has Abstractpub_date
2005-06-01 00:00:00pages
499-508issue
6eissn
0008-4212issn
1205-7541pii
y05-036journal_volume
83pub_type
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journal_title：Canadian journal of physiology and pharmacology
pub_type： 杂志文章
doi：10.1139/y86-053
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journal_title：Canadian journal of physiology and pharmacology
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journal_title：Canadian journal of physiology and pharmacology
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journal_title：Canadian journal of physiology and pharmacology
pub_type： 杂志文章,评审
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更新日期：1991-02-01 00:00:00
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