Cytochrome P450 3A and 2B6 in the developing kidney: implications for ifosfamide nephrotoxicity

Abstract

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.

Isolation and phylogeny of novel cytochrome P450 genes from tunicates (Ciona spp.): A CYP3 line in early deuterostomes?

“…The Ciona genes also are expressed at different stages of development indicating a potential stage-specific functional role. Previous studies have demonstrated the developmental expression of multiple CYP3As (Stevens et al, 2003;Aleksa et al, 2005). Thus, CYP3A4 and CYP3A7 are expressed specifically in adult and fetal human livers, respectively (Komori et al, 1990), and distinct CYP3As are differentially expressed in embryonic and adult fish (Kullman and Hinton, 2001).…”

Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

“…CYP3A5 and CYP2B6 activities are present in kidney and liver (12,13). The calculated [CAA] in rat renal cortex is f15 Amol/L following daily injection of 50 mg/kg IFO for 5 days.…”

“…IFO must be oxidized by cytochrome 3A5 (CYP3A5) and CYP2B6 oxidase to acquire an antineoplastic activity (11,12). The oxidation of IFO occurs via two major routes: (a) at the cyclic carbon-4, resulting in the formation of 4-OH-IFO, which is then decomposed to isophosphoramide mustard (IPM) and acrolein (1,2); and (b) via the side chain dechlorethylation, which leads to formation of chloroacetaldehyde (CAA).…”

“…The latter may account for up to 50% of IFO metabolism (1,2). Because CYP3A5 and CYP2B6 activity is present in kidney and liver (12,13), CAA can be produced in renal proximal tubules, the site of IFO-induced nephrotoxicity.…”

Renal Vulnerability to Drug Toxicity

“…Elevated tissue concentration of these toxins promotes injury through both direct toxicity and ischemic damage (reduced prostaglandins, increased thromboxane). Biotransformation of drugs, xenobiotics, and other substances by multiple renal enzyme systems, including CYP450 and flavin-containing monooxygenases, favors the formation of toxic metabolites and reactive oxygen species (33)(34)(35). The presence of these byproducts of metabolism tilts the balance in favor of oxidative stress, which outstrips natural antioxidants and increases renal injury via nucleic acid alkylation or oxidation, protein damage, lipid peroxidation, and DNA strand breaks (33)(34)(35).…”