Functional and toxicological consequences of metabolic bioactivation of methapyrilene via thiophene S-oxidation: Induction of cell defence, apoptosis and hepatic necrosis.
Methapyrilene, [N,N-dimethyl-N'-pyridyl-N'(2-thienylmethyl)-1,2-ethanediamine] (MP) was withdrawn from, clinical use due to reported periportal hepatic necrosis and hepatocarcinogenicity in the rat, via S-oxidation of the thiophene group. In this study MP is used as a model hepatotoxin to further characterise the functional consequences of S-oxidation of the thiophene group in vivo, in rat models and in vitro, in freshly isolated rat hepatocyte suspensions. In vivo histological studies revealed the early depletion of glutathione (GSH), which was confined to the damaged periportal area, in contrast to an increase in GSH levels in the centrilobular region. Additionally, the induction of cell defence was demonstrated by an increase in the protein levels of heme-oxygenase 1 (HO-1) and glutamate cysteine ligase, catalytic subunit (GCLC) in vivo. Histological examination demonstrated that cytotoxicity progresses initially via apoptosis before an increase in necrosis over the 3-day administration. An apoptotic-like mechanism was observed in vitro via the measurement of cytochrome c release and caspase activation.


CONCLUSIONS
This study provides evidence for a complex pathway of MP-induced hepatotoxicity which progresses through early adaptation, apoptosis, necrosis and inflammation, all underpinned by the zonal induction and depletion of GSH within the liver.
Mercer
Amy E
AE
MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, The University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, UK.
Regan
Sophie L
SL
Hirst
Charlotte M
CM
Graham
Emma E
EE
Antoine
Daniel J
DJ
Benson
Craig A
CA
Williams
Dominic P
DP
Foster
John
J
Kenna
J Gerry
JG
Park
B Kevin
BK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008701:Methapyrilene / Q000493:pharmacokinetics / Q000633:toxicity*; D009336:Necrosis; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D013876:Thiophenes / Q000378:metabolism*
D013876:Thiophenes; D008701:Methapyrilene; D051547:Heme Oxygenase-1; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione