Hepatotoxicity of the isomers of cyclo(Trp-Pro).
The hepatotoxicity of the novel cyclic dipeptide cyclo(Trp-Pro), which has shown potential usage in various pharmacological fields, had not been assessed. Further studies on the isomers of this cyclic dipeptide (cyclo(L-Trp-L-Pro), cyclo-(L-Trp-D-Pro), cyclo(D-Trp-L-Pro) and cyclo(D-Trp-D-Pro)) revealed further biological activities. The assessment of hepatotoxicity of these isomers was thus warranted. In vitro screens were performed on primary isolated rat hepatocytes, the Chang liver and N-2-alpha cell lines. In vivo screening involved the assessment of serum levels of lactate dehydrogenase, aspartate transaminase, ATP, Ca2+ and albumin after intraperitoneal injection over a 1 and 5 day period in the rat model. Liver samples were also obtained for the assessment of lipid peroxidation. It was found that only cyclo(D-Trp-L-Pro) was hepato-specific in its action, while the other isomers were not. The greatest effect on any biochemical or physiological parameter was noted after 5 days. LDH secretion was greatly increased in the presence of cyclo(L-Trp-L-Pro) and cyclo-(L-Trp-D-Pro) (p < 0.05). Significantly increased levels of lipid peroxidation were observed in all the isomer-treated samples (p < 0.05), while Ca2+ concentrations were decreased at day 5. Decreased protein synthesis was noted in the presence of all the isomers at day 1. These results indicate the potential harm involved in the administration of the isomers, which may limit their potential usage in the treatment of various diseases.
D000255:Adenosine Triphosphate / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002469:Cell Separation; D002470:Cell Survival; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D004151:Dipeptides / Q000633:toxicity*; D004734:Energy Metabolism / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects; D007536:Isomerism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D010456:Peptides, Cyclic / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D012709:Serum Albumin / Q000378:metabolism
D004151:Dipeptides; D010456:Peptides, Cyclic; D012709:Serum Albumin; C118539:cyclo(tryptophyl-prolyl); D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D002118:Calcium