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.
CYP2J2 is abundant in cardiomyocytes and is involved in the metabolism of arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs), which affect multiple cell functions. In this study, we investigated the effect of overexpression of CYP2J2 on cardiac L-type Ca 2ϩ currents (I Ca ) in adult transgenic mice. Cardiac-specific overexpression of CYP2J2 was achieved using the ␣-myosin heavy chain promoter. I Ca was recorded from isolated ventricular cardiomyocytes. Compared with the wildtype cardiomyocytes (n ϭ 60), the density of I Ca was significantly increased by 40 Ϯ 9% in the CYP2J2 transgenic cardiomyocytes (n ϭ 71; P Ͻ 0.001). N-Methylsulfonyl-6-(2-proparglyloxyphenyl)hexanamide (MS-PPOH), a specific inhibitor of EET biosynthesis, and clotrimazole, a cytochrome P450 inhibitor, significantly reduced I Ca in both wild-type and transgenic cardiomyocytes; however, MS-PPOH inhibited I Ca to a greater extent in the CYP2J2 transgenic cells (n ϭ 10) than in the wild-type cells (n ϭ 10; P Ͻ 0.01). Addition of 11,12-EET significantly restored I Ca in MS-PPOH-treated cells. Intracellular dialysis with either of two inhibitory monoclonal antibodies against CYP2J2 significantly reduced I Ca in both wild-type and transgenic mice. Membrane-permeable 8-bromo-cAMP and the -adrenergic agonist isoproterenol significantly reversed the monoclonal antibody-induced inhibition of I Ca . In addition, the total protein level of the ␣1 subunit of the Ca v 1.2 L-type Ca 2ϩ channel was not altered in CYP2J2 transgenic hearts, but the phosphorylated portion was markedly increased. In conclusion, overexpression of CYP2J2 increases I Ca in CYP2J2 transgenic cardiomyocytes via a mechanism that involves cAMPprotein kinase A-dependent phosphorylation of the L-type Ca 2ϩ channel.
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