Ontogeny of ifosfamide nephrotoxicity.
Published: 2004
Language: eng
Number of pages: 168
Description: Drug-induced nephrotoxicity may adversely affect the health and well-being of children, especially when the developing kidney is exposed to toxic agents that may lead to acute glomerular, tubular or combined toxicity. Repeated administration of such agents (e.g., cancer chemotherapy) may lead to acute or chronic renal damage often associated with devastating effects on long-term child health. Loebstein et al. has shown that the cancer chemotherapeutic ifosfamide (IF) causes serious renal damage substantially more in younger children (less than 3 years of age) than among older children. The mechanism of the age-related IF-induced renal damage is not known. This thesis demonstrates that the localized metabolism of IF in the kidney and the ensuing production of nephrotoxic chloroacetaldehyde results in oxidative stress. The major hypothesis underlying this work is that there is renal ontogeny in the expression and activity of CYP enzymes responsible for IF metabolism and resultant nephrotoxicity. The presence of CYP3A4, 3A5 and 2136 was confirmed in human fetal, pediatric and adult kidney as was the metabolism of IF (both R-IF and  S-IF) by renal microsomes to 2-dechloroethylifosfamide (2-DCEIF) and 3-dechloroethylifosfamide (3-DCEIF). There was a correlation between the  S-IF metabolite R-3-DCEIF and CYP3A4/5 and between  S-2-DCEIF with CYP2136 enzyme levels. Ontogeny in CYP3A expression and 2B22 activity was assessed in piglets ranging in age from 1 day to adult. Kidney CYP3A expression peaked in age consistent with toddlerhood as did the metabolic activity, corroborating the clinical experience in children. This is the first documentation of renal CYP ontogeny and of renal drug metabolism, leading to age-dependent nephrotoxicity.
Notes: Adviser:  Gideon Koren.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 5093.