Role of the renal cysteine conjugate beta-lyase pathway in inhaled compound A nephrotoxicity in rats.
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.
Kharasch
E D
ED
Department of Anesthesiology, University of Washington, Seattle 98195, USA. kharasch@u.washington.edu
Hoffman
G M
GM
Thorning
D
D
Hankins
D C
DC
Kilty
C G
CG
D018685:Anesthetics, Inhalation / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001711:Biotransformation; D013437:Carbon-Sulfur Lyases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004987:Ethers / Q000493:pharmacokinetics / Q000633:toxicity*; D006845:Hydrocarbons, Fluorinated / Q000493:pharmacokinetics / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
D018685:Anesthetics, Inhalation; D015415:Biomarkers; D004791:Enzyme Inhibitors; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase