Cytochrome P450 3A and 2B6 in the developing kidney: implications for ifosfamide nephrotoxicity.
Repeated administration of agents (e.g., cancer chemotherapy) that can cause drug-induced nephrotoxicity may lead to acute or chronic renal damage. This will 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. We have previously 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. Our major hypothesis is that renal CYP P450 expression and activity are responsible for IF metabolism to the nephrotoxic chloroacetaldehyde. Presently, the ontogeny of these catalytic enzymes in the kidney is sparsely known. The presence of CYP3A4, 3A5 and 2B6 was investigated in human fetal, pediatric and adult kidney as was the metabolism of IF (both R-IF and S-IF enantiomers) by renal microsomes to 2-dechloroethylifosfamide (2-DCEIF) and 3-dechloroethylifosfamide (3-DCEIF). Our analysis shows that CYP 3A4 and 3A5 are present as early as 8 weeks of gestation. IF is metabolized in the kidney to its two enantiomers. This metabolism can be inhibited with CYP 3A4/5 and 2B6 specific monoclonal inhibitory antibodies, whereby the CYP3A4/5 inhibitory antibody decreased the production of R-3-DCEIF by 51%, while the inhibitory CYP2B6 antibody decreased the production of S-2-DCEIF and S-3-DCEIF by 44 and 43%, respectively, in patient samples. Total renal CYP content is approximately six-fold lower than in the liver.
Aleksa
Katarina
K
Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
Matsell
Doug
D
Krausz
Kris
K
Gelboin
Harry
H
Ito
Shinya
S
Koren
Gideon
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D005333:Fetus / Q000201:enzymology; D006801:Humans; D007069:Ifosfamide / Q000009:adverse effects / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D007150:Immunohistochemistry; D007223:Infant; D007668:Kidney / Q000187:drug effects / Q000196:embryology* / Q000201:enzymology* / Q000378:metabolism; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000276:immunology / Q000378:metabolism*; D013237:Stereoisomerism
D000911:Antibodies, Monoclonal; D018906:Antineoplastic Agents, Alkylating; C064445:dechloroethylcyclophosphamide; D003520:Cyclophosphamide; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; C038007:dechloroethylifosfamide; D007069:Ifosfamide