Role of the Renal Cysteine Conjugate β-Lyase Pathway in Inhaled Compound A Nephrotoxicity in Rats

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Abstract
Background: The sevoflurane degradation product compound A is nephrotoxic in rats and undergoes metabolism to glutathione and cysteine S-conjugates, with further metabolism by renal cysteine conjugate beta-lyase to reactive intermediates. Evidence suggests that toxicity is mediated by renal uptake of compound A S-conjugates and metabolism by beta-lyase. Previously, inhibitors of the beta-lyase pathway (aminooxyacetic acid and probenecid) diminished the nephrotoxicity of intraperitoneal compound A. This investigation determined inhibitor effects on the toxicity of inhaled compound A. Methods: Fischer 344 rats underwent 3 h of nose-only exposure to compound A (0-220 ppm in initial dose-response experiments and 100-109 ppm in subsequent inhibitor experiments). The inhibitors (and targets) were probenecid (renal organic anion transport mediating S-conjugate uptake), acivicin (gamma-glutamyl transferase), aminooxyacetic acid (renal beta-lyase), and aminobenzotriazole (cytochrome P450). Urine was collected for 24 h, and the animals were killed. Nephrotoxicity was assessed by histology and biochemical markers (serum BUN and creatinine; urine volume; and excretion of protein, glucose, and alpha-glutathione-S-transferase, a predominantly proximal tubular cell protein). Results: Compound A caused dose-related proximal tubular cell necrosis, diuresis, proteinuria, glucosuria, and increased alpha-glutathione-S-transferase excretion. The threshold for toxicity was 98-109 ppm (294-327 ppm-h). Probenecid diminished (P < 0.05) compound A-induced glucosuria and excretion of alpha-glutathione-S-transferase and completely prevented necrosis. Aminooxyacetic acid diminished compound A-dependent proteinuria and glucosuria but did not decrease necrosis. Acivicin increased nephrotoxicity of compound A, and aminobenzotriazole had no consistent effect on nephrotoxicity of compound A. Conclusions: Nephrotoxicity of inhaled compound A in rats was associated with renal uptake of compound A S-conjugates and cysteine conjugates metabolism by renal beta-lyase. Manipulation of the beta-lyase pathway elicited similar results, whether compound A was administered by inhalation or intraperitoneal injection. Route of administration does not apparently influence nephrotoxicity of compound A in rats.