Renal ontogeny of ifosfamide nephrotoxicity

Abstract

Ifosfamide (IF) -induced nephrotoxicity adversely affects the health and well-being of children with cancer. We have recently shown age-dependent nephrotoxicity of IF, with younger children (less than 3 years of age) substantially more vulnerable. The mechanisms leading to this age-related IF-induced renal damage have not been identified. The hypothesis underlying this work was that there is renal ontogeny in the expression and activity of cytochrome P450 (CYP) enzymes responsible for IF metabolism to the nephrotoxic chloroacetaldehyde. The presence of renal CYP3A and 2B22 activity was evaluated in pigs between 1 day of age to adulthood, as was the metabolism of IF by renal microsomes to 2- and 3-dechloroethylifosfamide (2-DCEIF and 3-DCEIF). Kidney CYP3A mRNA expression peaked at 15 to 60 days (0.7–76±0.19 CYP3A/actin ratio) (P<0.001). Subsequently, this level decreased to adult values (0.54±0.03 CYP3A/actin ratio) (P=0.04). In a similar manner, there was an increase in IF metabolic rate between young (18±2 pM/mg protein/min) vs adults (12.2±0.17 pM/mg protein/min) (P=0.002). This is the first documentation of ontogeny of renal CYP3A and of renal IF metabolism. These data suggest that age-dependent IF nephrotoxicity is, at least in part, due to ontogeny in the production chloroacetaldehyde. Clinical Pharmacology & Therapeutics (2005) 77, P80–P80; doi: 10.1016/j.clpt.2004.12.198