Cytosolic C-S lyase activity in human kidney samples-relevance for the nephrotoxicity of halogenated alkenes in man.
Human renal cortex cytosolic samples were screened for C-S lyase (EC 4.4.1.13) activity using cysteine conjugates of halogenated aliphatic and aromatic hydrocarbons as substrates. Cystosolic activity was greatest with S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC) (72.0 +/- 26.8 and 74.4 +/- 38.3 nmol pyruvate formed/mg protein/120 min. respectively). Less than five fold inter-individual variation was observed. In contrast to the low C-S lyase activity detectable in rat cytosol, no cleavage of the aromatic conjugates S-(2-benzothiazolyl)-L-cysteine (BTC), S-(2,3,5,6-tetrachlorophenyl)-L-cysteine (TCPC) and S-(4-bromophenyl)-L-cysteine (4-BPC) was detectable in human cytosol. Structure-activity relationships showed that increasing the fluorinated carbon chain length of the halogenated hydrocarbon species decreased conjugate cleavage by C-S lyase. The position and number of fluorine and chlorine atoms on the parent hydrocarbon determined the extent of cysteine conjugate C-S cleavage. Activity increased with an increase in fluorine and chlorine substitution and shortening of carbon chain length in the rat, although in human cytosol an increase in chlorine substitution resulted in decreased activity.
McCarthy
R I
RI
Department of Medicine, University of Aberdeen, England.
Lock
E A
EA
Hawksworth
G M
GM
D000475:Alkenes / Q000633:toxicity; D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology*; D008190:Lyases / Q000032:analysis*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D000475:Alkenes; D015415:Biomarkers; D006846:Hydrocarbons, Halogenated; D008190:Lyases; C033511:carbon-sulfur lyase