L-alanine-glyoxylate aminotransferase II of rat kidney and liver mitochondria possesses cysteine S-conjugate beta-lyase activity: a contributing factor to the nephrotoxicity/hepatotoxicity of halogenated alkenes?
Several halogenated alkenes are metabolized in part to cysteine S-conjugates, which are mitochondrial toxicants of kidney and, to a lesser extent, other organs. Toxicity is due to cysteine S-conjugate beta-lyases, which convert the cysteine S-conjugate into pyruvate, ammonia and a reactive sulphur-containing fragment. A section of the human population is exposed to halogenated alkenes. To understand the health effects of such exposure, it is important to identify cysteine S-conjugate beta-lyases that contribute to mitochondrial damage. Mitochondrial aspartate aminotransferase [Cooper, Bruschi, Iriarte and Martinez-Carrion (2002) Biochem. J. 368, 253-261] and mitochondrial branched-chain aminotransferase [Cooper, Bruschi, Conway and Hutson (2003) Biochem. Pharmacol. 65, 181-192] exhibit beta-lyase activity toward S -(1,2-dichlorovinyl)-L-cysteine (the cysteine S-conjugate of trichloroethylene) and S -(1,1,2,2-tetrafluoroethyl)-L-cysteine (the cysteine S-conjugate of tetrafluoroethylene). Turnover leads to eventual inactivation of these enzymes. Here we report that mitochondrial L-alanine-glyoxylate aminotransferase II, which, in the rat, is most active in kidney, catalyses cysteine S-conjugate beta-lyase reactions with S -(1,1,2,2-tetrafluoroethyl)-L-cysteine, S -(1,2-dichlorovinyl)-L-cysteine and S -(benzothiazolyl-L-cysteine); turnover leads to inactivation. Previous workers showed that the reactive-sulphur-containing fragment released from S -(1,1,2,2-tetrafluoroethyl)-L-cysteine and S -(1,2-dichlorovinyl)-L-cysteine is toxic by acting as a thioacylating agent - particularly of lysine residues in nearby proteins. Toxicity, however, may also involve 'self-inactivation' of key enzymes. The present findings suggest that alanine-glyoxylate aminotransferase II may be an important factor in the well-established targeting of rat kidney mitochondria by toxic halogenated cysteine S-conjugates. Previous reports suggest that alanine-glyoxylate aminotransferase II is absent in some humans, but present in others. Alanine-glyoxylate aminotransferase II may contribute to the bioactivation (toxification) of halogenated cysteine S-conjugates in a subset of individuals exposed to halogenated alkenes.
Cooper
Arthur J L
AJ
Department of Biochemistry, Weill Medical College of Cornell University, 1600 York Avenue, New York, NY 10021, USA. acooper@burke.org
Krasnikov
Boris F
BF
Okuno
Etsuo
E
Jeitner
Thomas M
TM
D000475:Alkenes / Q000633:toxicity; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D013437:Carbon-Sulfur Lyases / Q000378:metabolism*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity; D006845:Hydrocarbons, Fluorinated / Q000378:metabolism; D006846:Hydrocarbons, Halogenated / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D008930:Mitochondria, Liver / Q000201:enzymology*; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D000637:Transaminases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000378:metabolism; D005466:Fluorocarbons
D000475:Alkenes; D000596:Amino Acids; D013437:Carbon-Sulfur Lyases; D003545:Cysteine; D004785:Environmental Pollutants; D006845:Hydrocarbons, Fluorinated; D006846:Hydrocarbons, Halogenated; D019289:Pyruvic Acid; D000637:Transaminases; D015091:beta-Alanine; C006977:3-chloroalanine; C064116:S-(1,1,2,2-tetrafluoroethyl)cysteine; D005466:Fluorocarbons; C019635:Alanine-glyoxylate transaminase; C108902:cysteine-S-conjugate beta-lyase