C-S lyase enzymes catalyse the generation of mutagenic and/or cytotoxic thiols from cysteine conjugated xenobiotics. These cysteine conjugates are produced subsequent to glutathione conjugations as a metabolic step in the mercapturic acid pathway, traditionally thought of as a pathway solely associated with detoxification. Human Chang liver (HCL) cells were challenged with a range of cysteine conjugates demonstrated to be substrates for human hepatic C-S lyases. The cellular toxicity of these compounds was determined and it was observed that the rank order of substrate toxicity obtained for the HCL cells followed the rank order of C-S lyase activity of the substrates in a freshly isolated mitochondrial fraction of human tissue. The presence of C-S lyase activity was also established in this cell line.
Get full access to this article
View all access options for this article.
References
1.
Green T. & Odum J.Structure/activity studies on the nephrotoxic and mutagenic action of cysteine conjugates of chloro- and fluoroalkenes. Chemico-Biological Interactions1985; 54: 15-31.
2.
Shaw PN & Blagbrough ISCysteine conjugate β-lyase II: Isolation, properties and structure-activity relationships. In Sulphur-Containing Drugs and Related Organic Compounds, vol 2B, Damani, L.A. (ed). Chichester, Ellis Horwood, 189, pp. 135-155.
Lash LH, Nelson RM, van Dyke RA & Anders MWPurification and characterization of human kidney cysteine conjugate β-lyase activity. Drug Metabolism and Disposition1990; 18: 50-5.
5.
Tomisawa H., Ichihara S., Fukazawa H., Ichimoto N., Tateishi M. & Yamamoto I.Purification and characterisation of human hepatic cysteine-conjugate β-lyase . Biochemical Journal1986; 235: 569-75.
6.
Buckberry LD , Blagbrough IS, Bycroft BW & Shaw PNKynurenine aminotransferase in human liver: identity with human hepatic C-S lyase activity and a physiological role for this enzyme. Toxicology Letters1992 ; 60: 241-6.
7.
Lash LH & Anders MWUptake of nephrotoxic S-conjugates by isolated rat renal proximal tubular cells. Journal of Pharmacology and Experimental Therapeutics1989; 248: 521-7.
8.
Schnellmann RG, Lock EA & Mandel LJA mechanism of S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine toxicity to rabbit renal proximal tubules. Toxicology and Applied Pharmacology1987; 90: 513-21.
9.
Stevens JL, Hayden P. & Taylor G.Studies on the mechanism of S-cysteine conjugate metabolism and toxicity in rat liver, kidney and a cell culture model. Advances in Experimental Biology and Medicine1986; 197: 381-90.
10.
Bridges JW, Benford DJ & Hubbard SAThe design and use of in vitro toxicity tests. In: Animals in Scientific Research: An effective substitute for man? Turner, P (ed), London, Macmillan, 1983, p. 47.
11.
McKinney LL, Picken JC, Weakley FB et al. Possible toxic factor of trichloroethylene extracted soybean oil meal. Journal of theAmerican Chemical Society1959; 81: 909-15.
12.
Dohn DR & Anders MWAssay of cysteine conjugate β-lyase activity with S-(benzothiazolyl)cysteine as the substrate. Analytical Biochemistry1982; 120: 379-86.
13.
Gandolfi AJ , Nagle RB, Soltis JJ & Plescia FHNephrotoxicity of halogenated vinyl cysteine compounds. Research Communications in Chemical Pathology and Pharmacology1981; 33: 249-61.
14.
Parke, DV & Williams RTStudies in detoxification 38: The metabolism of benzene. Biochemical Journal1951; 48: 624-9.
15.
Iselt M., Holtei W. & Hilgard P.The tetrazolium dye assay for rapid in vitro assessment of cytotoxicity . Arzneimittel-Forschung1989; 39: 747-9.
16.
Gutmann I. & Wahlefeld AWL-[+]-Lactate: determination with lactate dehydrogenase and NAD. In: Methods of Enzymatic Analysis, vol 3, Bergmeyer HU (ed), New York, Academic Press, 1974, pp. 1464-1472.
17.
Tanizawa K., Asada Y. & Soda K.L-Kynurenine transaminase from Hansenula schneggii. In: Methods in Enzymology, vol 113, Meister A (ed), London, Academic Press, 1985, pp. 90-5.
18.
Hartline RAKynurenine aminotransferase from kidney supernatant. In: Methods in Enzymology, vol 113, Meister A (ed), London, Academic Press, 1985, pp. 664-72.
19.
Lowry OH, Rosebrough NJ, Farr AL & Randall RJProtein measurement with the Folin phenol reagent. Journal of Biological Chemistry1951; 193: 265-75.
20.
Tateishi M., Suzuki S. & Shimizu H.Cysteine conjugate β-lyase from rat liver. Journal of Biological Chemistry1978; 253: 8854-9.
Anders MW, Lash LH, Dekant FW, Elfarra AA & Dohn DRBiosynthesis and biotransformation of glutathione S-conjugates to toxic metabolites . CRC Critical Reviews in Toxicology1988; 18: 311-41.
23.
Lock EAStudies on the mechanisms of nephrotoxicity and nephrocarcinogenicity of halogenated alkenes. CRC Critical Reviews in Toxicology1988; 19: 23-42.
24.
Chen JC, Stevens JL, Trifillis AL & Jones TWRenal cysteine conjugate β-lyase mediated toxicity studies with primary cultures of human proximal tubular cells. Toxicology and Applied Pharmacology1990; 103: 463-73.
25.
Commandeur JN, Oostendorp RA, Schoofs PR, Xu B. & Vermeulen Npe.Nephrotoxicity and hepatotoxicity of 1,1-dichloro-2,2-difluoroethylene in the rat. Indications for differential mechanisms of bioactivation. Biochemical Pharmacology1987; 36: 4229-37.
26.
Blagbrough IS, Buckberry LD, Bycroft BW & Shaw PNStructure activity relationship studies of bovine C-S lyase enzymes. Pharmaceutical and Pharmacology Letters1992; 1: 93-6.
27.
Wallach DPThe inhibition of γ-aminobutyric-α-ketoglutaric acid transaminase in vitro and in vivo by amino-oxyacetic acid. Biochemical Pharmacology1960; 5: 166-7.
28.
Beeler T. & Churchich JEReactivity of the phosphopyridoxal groups of cystathionase. Journal of Biological Chemistry1976; 251: 5267-71.
29.
Parker VHA biochemical study of the toxicity S-(1,2-dichlorovinyl)-L-cysteine . Food and Cosmetic Toxicology1965; 3: 75-84.
30.
Stonard MD & Parker VH 2-Oxoacid dehydrogenases in rat liver mitochondria as the site of action of S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)-3-mercaptopropionic acid. Biochemical Pharmacology1971; 20: 2417-27.
31.
Stonard MD & Parker VHMetabolism of S-(1,2-dichlorovinyl)-L-cysteine by rat liver mitochondria . Biochemical Pharmacology1971; 20: 2428-37.
32.
Stonard MDFurther studies on the site and mechanism of action of S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)-3-mercaptopropionic acid in rat liver. Biochemical Pharmacology1973; 22: 1329-35.
33.
Jones TW, Wallin A., Gerdes RJ, Ormstad K. & Orrenius S.S-Pentachlorobutadienyl-glutathione nephrotoxicity. Federation Proceedings1986; 45: 1933.
34.
Jones TW, Wallin A., T hor H., Gerdes RJ, Ormstad K. & Orrenius S.The mechanism of pentachlorobutadienyl-glutathione nephrotoxicity: studies with isolated rat renal epithelial cells. Archives of Biochemistry and Biophysics1986; 251: 504-13.
35.
Lash LH, Elfarra AA & Anders MWRenal cysteine conjugate β-lyase: bioactivation of nephrotoxic cysteine conjugates in mitochondrial outer membrane. Journal of Biological Chemistry1986; 261: 5930-5.
36.
Lash LH & Anders MWCytotoxicity of S-(1,2-dichlorovinyl)-L-glutathione and S-(1,2-dichlorovinyl)-L-cysteine in rat kidney cells. Journal of Biological Chemistry1986; 261:13076-81.
37.
Lock EA & Schnellmann RGThe effect of haloalkene cysteine conjugates on rat renal glutathione reductase and lipoyl dehydrogenase activities. Toxicology and Applied Pharmacology1990; 104: 180-90.
38.
Schnellmann RG, Cross TJ & Lock EAPentachlorobutadienyl-L-cysteine uncouples oxidative phosphorylation by dissipating the proton gradient. Toxicology and Applied Pharmacology1989; 100: 498-505.
39.
Stevens JLIsolation and characterization of an enzyme with both cysteine conjugate β-lyase activity and kynureninase activity. Journal of Biological Chemistry1985; 260: 7945-50.
40.
Soda K. & Tanizawa K.Kynureninases: enzymological properties and regulation mechanism. Advances in Enzymology and Related Areas of Molecular Biology1979; 49: 1-40.
