Dose-dependent induction or depression of cysteine conjugate beta-lyase in rat kidney by N-acetyl-S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine.
The influence of N-acetyl-S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine (NAc-PCBD) on cysteine conjugate beta-lyase in female rat kidney has been examined. After a single, non-nephrotoxic dose of NAc-PCBD (3 mg/kg), cytosolic beta-lyase enzyme activity was increased 1.5 to 3-fold commensurate with a corresponding increase in enzyme protein levels as assessed by both Western blot and ELISA analyses. Using a cDNA probe for beta-lyase, this induction was found to be accompanied by an increase in the cognate mRNA. In contrast, a higher, nephrotoxic dose of NAc-PCBD (10 mg/kg) decreased all the above parameters. These effects appeared to be specific to the cytosolic form of the enzyme as no changes in kidney mitochondrial beta-lyase or enzyme protein levels were observed. Repeated dosing with the lower dose level (3 mg/kg) resulted in either no change, or in some instances, a reduction in the above parameters, suggesting an accumulation of the xenobiotic and a masking of the induction phenomenon. The molecular mechanisms underlying these observations are discussed in terms of the nephrotoxicity of halogenated xenobiotics.
MacFarlane
M
M
Molecular Toxicology Group, School of Biological Sciences, University of Surrey, Guildford, UK.
Schofield
M
M
Parker
N
N
Roelandt
L
L
David
M
M
Lock
E A
EA
King
L J
LJ
Goldfarb
P S
PS
Gibson
G G
GG
D000111:Acetylcysteine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D001806:Blood Urea Nitrogen; D015153:Blotting, Western; D002070:Butadienes / Q000008:administration & dosage / Q000633:toxicity*; D013437:Carbon-Sulfur Lyases; D003600:Cytosol / Q000201:enzymology; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology*; D008190:Lyases / Q000032:analysis / Q000096:biosynthesis*; D008928:Mitochondria / Q000201:enzymology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D000637:Transaminases / Q000032:analysis
D002070:Butadienes; D012333:RNA, Messenger; C049739:N-acetyl-S-pentachloro-1,3-butadienylcysteine; D000637:Transaminases; C020656:glutamine-pyruvate aminotransferase; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase; D000111:Acetylcysteine