jbp-485 and Chemical-and-Drug-Induced-Liver-Injury

The cyclic dipeptides generally present lower affinity toward intestinal oligopeptide transporter 1 (PEPT1) than the linear dipeptides. JBP485 (cyclo(l-Hyp-l-Ser)) is a low-affinity substrate of PEPT1 with poor oral bioavailability. However, JBP923 (l-Hyp-l-Ser) is a high-affinity substrate of PEPT1 with high oral absorption. We hypothesize that the bioactivatable pseudo-tripeptidization prodrug strategy is promising to increase the affinity of cyclic dipeptides toward PEPT1. To test our hypothesis, we design five amino acid ester prodrugs of JBP485. Compared with JBP485, the optimal prodrug (JBP485-3-CH

Topics: Administration, Oral; Animals; Antiviral Agents; Caco-2 Cells; Cell Membrane Permeability; Chemical and Drug Induced Liver Injury; Dogs; Dose-Response Relationship, Drug; Humans; Molecular Docking Simulation; Molecular Structure; Peptide Transporter 1; Peptides, Cyclic; Prodrugs; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

Cyclo-trans-4-l-hydroxyprolyl-l-serine (JBP485) was first isolated from Laennec (hydrolysate of human placenta). We thought it valuable to clarify the anti-hepatitis molecular mechanism of JBP485 to develop a new oral anti-hepatitis drug.. We investigated the hepatoprotective effect of JBP485 on immune-mediated, concanavalin A (Con A)-induced liver injury in mice. Mice were administered JBP485 before and after injection of Con A (10 mg/kg). Eight hours after Con A, the cytosolic enzyme activity (alanine aminotransferase, lactate dehydrogenase) in serum, and the enzyme activity or concentration (superoxide dismutase, maleic dialdehyde, myeloperoxidase, nitric oxide) in liver homogenate were determined. The liver slices were investigated to observe changes in histology. The effect of JBP485 on level of tumour necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) in liver were detected by immunohistochemistry. Hepatocyte DNA fragmentation was assayed by agarose gel electrophoresis and the transcription of the genes bax and bcl-2 in hepatocytes was determined by reverse transcription-polymerase chain reaction.. Con A increased the cytosolic and liver homogenate enzyme activity, and the concentrations of ICAM-1 and TNF-alpha, which were significantly inhibited by JBP485 administration. Also, the increase in DNA fragmentation and decrease in bcl-2/bax mRNA induced by Con A administration were significantly inhibited by JBP485.. These results indicated that immune-mediated liver damage can be prevented by JBP485, and that this is mainly associated with immunomodulatory effects on T cells and adhesion molecules, antioxidation, and inhibition of apoptosis.

Topics: Animals; Apoptosis; Chemical and Drug Induced Liver Injury; Concanavalin A; Cytosol; DNA Fragmentation; Electrophoresis, Agar Gel; Female; Hepatocytes; Immunohistochemistry; Immunologic Factors; Intercellular Adhesion Molecule-1; Mice; Mice, Inbred BALB C; Peptides, Cyclic; Protective Agents; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

It has been a desire to develop orally effective therapeutic agents that restore the liver function in chronic injury. Here we demonstrated that trans-4-L-hydroxyprolyl-L-serine (JBP923) and cyclo-trans-4-L-hydroxyprolyl-L-serine (JBP485), which was previously isolated from hydrolysate of human placenta, exhibit potent antihepatitis activity after their oral administration. The increase in bilirubin concentration and activities of liver cytosolic enzymes in serum caused by alpha-naphthylisothiocyanate intoxication in rats were significantly countered both after i.v. and oral administration of these dipeptides, whereas glycyrrhizin, which has been used in the treatment of chronic hepatitis, is active only after its i.v. administration. Antihepatitis activity of dipeptides results, at least partially, from their direct effect on hepatocytes because glutamic-oxaloacetic transaminase and lactate dehydrogenase activities in the medium of hepatotoxin-exposed primary cultured hepatocytes were reduced by these compounds. When comparing the plasma concentration-time profile of JBP923 after its i.v., oral, and portal vein injection, it is suggested that JBP923 is almost completely absorbed from gastrointestinal lumen, and hepatic first-pass removal is minor. JBP923 inhibited the proton-dependent transport of glycylsarcosine in brush-border membrane vesicles, suggesting that peptide transport system(s) may recognize JBP923. Thus, these dipeptides are potent antihepatitis reagents that are still active after oral administration and may be useful for clinical applications.

Topics: 1-Naphthylisothiocyanate; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbon Radioisotopes; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cytosol; Dipeptides; Gastric Mucosa; Glycyrrhizic Acid; Intestinal Absorption; Intestinal Mucosa; Intestines; Liver; Male; Microvilli; Peptides, Cyclic; Rabbits; Rats; Rats, Wistar