Cysteine conjugate beta-lyase-dependent biotransformation of the cysteine S-conjugates of the sevoflurane degradation product compound A in human, nonhuman primate, and rat kidney cytosol and mitochondria.
BACKGROUND
2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (compound A) is a fluorinated alkene formed by the degradation of sevoflurane in the anesthesia circuit. Compound A is toxic to the kidneys in rats and undergoes glutathione-dependent metabolism in vivo. Several nephrotoxic halogenated alkenes also undergo cysteine conjugate beta-lyase-dependent biotransformation. These experiments were designed to test the hypothesis that cysteine S-conjugates of compound A undergo beta-lyase-dependent biotransformation.


METHODS
S-[2-(Fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-L-cysteine 4, S-[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-L-cysteine 5, and S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine 11 were incubated with rat, human, and nonhuman primate (cynomolgus, rhesus, and marmoset) kidney cytosol and mitochondria. beta-Lyase activity was determined by measuring pyruvate formation.


RESULTS
Compound A-derived conjugates 4 and 5 as well as conjugate 11, a positive control, were substrates for cytosolic and mitochondrial beta-lyase from human, nonhuman primate, and rat kidney. For all substrates, beta-lyase activity was highest in the rat and lowest in the human and was higher in cytosol than in mitochondria. Conjugate 11 was a much better substrate than conjugates 4 or 5. The biotransformation of conjugates 4, 5, and 11 was inhibited by the beta-lyase inhibitor (aminooxy)acetic acid and was stimulated by the amino group acceptor 2-keto-4-methylthiolbutyric acid, indicating a role for beta-lyase.


CONCLUSIONS
These data confirm the presence of beta-lyase activity in human and rat kidney and show that activity is also present in kidney tissue from nonhuman primates. The data also show that compound A-derived conjugates 4 and 5 undergo beta-lyase-catalyzed biotransformation. beta-Lyase activity in rat and nonhuman primate kidney tissue was 8 to 30 times and one- to three times, respectively, higher than in human kidney tissue.
Iyer
R A
RA
University of Rochester, Department of Pharmacology, New York 14642, USA.
Anders
M W
MW
D018685:Anesthetics, Inhalation / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D002144:Callithrix; D013437:Carbon-Sulfur Lyases; D004987:Ethers / Q000493:pharmacokinetics*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism*; D008190:Lyases / Q000378:metabolism; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
D018685:Anesthetics, Inhalation; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase