Biotransformation of l-CysteineS-Conjugates andN-Acetyl-l-CysteineS-Conjugates of the Sevoflurane Degradation Product Fluoromethyl-2,2-Difluoro-1-(trifluoromethyl)vinyl Ether (Compound A) in Human Kidney in Vitro: Interindividual Variability inN-Acetylation,N-Deacetylation, and β-Lyase-Catalyzed Metabolism

Abstract

This paper is available online at http://dmd.aspetjournals.org ABSTRACT:Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE; 1) is a fluoroalkene formed by the base-catalyzed degradation of the anesthetic sevoflurane. FDVE is nephrotoxic in rats. In both rats and humans, FDVE undergoes glutathione-dependent conjugation, cleavage to cysteine S-conjugates, and renal ␤-lyase-catalyzed metabolism to reactive intermediates, which may cause nephrotoxicity. Interindividual variability in renal metabolism of FDVE is unknown. Therefore, this investigation quantified ␤-lyase-cata-

Trichloroethylene: Mechanisms of Renal Toxicity and Renal Cancer and Relevance to Risk Assessment

“…Once inside the renal tubule cell the relative rates of blyase bioactivation, and N-acetylation and deacetylation of NAcDCVC will influence the extent of cellular injury. Human renal b-lyase can metabolize DCVC and there is about a fivefold inter-individual variation in the cytosolic enzyme activity with DCVC (Green et al, 1997) and S-[2-(fluoromethoxy)-1,3,3,3,-tetrafluoro-1-propenyl]-L-cysteine as substrates (Altuntas and Kharasch, 2002). The activity of the human mitochondrial enzyme with DCVC as substrate has not been reported.…”

“…The activity of the human mitochondrial enzyme with DCVC as substrate has not been reported. The N-acetyltransferases are known to be polymorphic, and with one haloalkene (S-[2-(fluoromethoxy)-1,3,3,3,-tetrafluoro-1propenyl]-L-cysteine; FDVE-cysteine) both the human renal cytosolic and microsomal enzymes exhibit a 60-70 fold interindividual variation in activity (Altuntas and Kharasch, 2002). Nacetyltransferase activity with DCVC as substrate has been measured in human renal cytosol; the kinetic data suggests a greater affinity for N-acetylation compared to b-lyase activity (Green et al, 1997).…”

“…Nacetyltransferase activity with DCVC as substrate has been measured in human renal cytosol; the kinetic data suggests a greater affinity for N-acetylation compared to b-lyase activity (Green et al, 1997). There is about a 7-fold inter-individual variation in the activity of human renal cytosolic N-deacetylase with FDVE-cysteine as substrate (Altuntas and Kharasch, 2002). Importantly the balance of N-acetylation versus N-deacetylation appears to lie in favor of deacetylation (2-50-fold).…”

“…Thus the greatest risk for renal injury would exist in those individuals with RENAL TOXICITY OF TRICHLOROETHYLENE a high N-deacetylation/N-acetylation ratio in combination with a high b-lyase/N-acetylation ratio. Working with 20 human kidney samples and FDVE-cysteine as substrate, Altuntas and Kharasch (2002) estimated that there could be up to a 50-fold individual variability in the rates of activation versus detoxification. Data with DCVC as substrate is not available, but the inter-individual variability is likely to be similar.…”

Glutathione‐Dependent Bioactivation

“…In contrast, the haloalkyl cysteine conjugates that contain only fluorines or chlorines are cytotoxic but not mutagenic, whereas those containing a bromine atom are also mutagenic (Finkelstein et al, ). These conjugates include several environmentally and clinically important compounds, such as chlorofluorocarbons that have been used as refrigerants (Yin et al, ) and degradation products of anesthetic agents such as sevoflurane (Iyer et al, ; Altuntas and Kharasch, ; Anders, ).…”