Renal ontogeny of ifosfamide nephrotoxicity.
Ifosfamide-induced nephrotoxicity adversely affects the health and well-being of children with cancer. We have recently shown age-dependent nephrotoxicity induced by ifosfamide, with younger children (<3 years) substantially more vulnerable. The mechanisms leading to this age-related ifosfamide-induced renal damage have not been identified. Underlying this work is the hypothesis that renal ontogeny is involved in the expression and activity of the cytochrome P450 (CYP) enzymes responsible for IF metabolism to the nephrotoxic chloroacetaldehyde. We evaluated renal CYP3A and 2B22 activity in pigs between the ages of 1 day and adulthood, as well as the metabolism of ifosfamide by renal microsomes to 2- and 3-dechloroethylifosfamide (2-DCEIF and 3-DCEIF, respectively). Kidney CYP3A messenger RNA expression peaked 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). Similarly, we detected an increase in the ifosfamide-metabolism rate between young (18 +/- 2 pmol/mg protein/min) and adult (12.2 +/- 0.17 pmol/mg protein/min) animals (P = 0.002). Ours is the first documentation of ontogeny of renal CYP3A and of renal ifosfamide metabolism. These data suggest that age-dependent ifosfamide nephrotoxicity is, at least in part, due to ontogeny in the production chloroacetaldehyde.
Aleksa
Katarina
K
Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Ontario, Canada.
Halachmi
Naomi
N
Ito
Shinya
S
Koren
Gideon
G
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002648:Child; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects*; D007674:Kidney Diseases / Q000139:chemically induced*; D008297:Male; D008861:Microsomes; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000378:metabolism; D013552:Swine
D018906:Antineoplastic Agents, Alkylating; C004656:chloroacetaldehyde; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; C025619:steroid 16-beta-hydroxylase; D010089:Oxidoreductases, N-Demethylating; D000079:Acetaldehyde; D007069:Ifosfamide