Structural features of prostanoid analogues involved in hepatocytes protection against CCl4-induced injury.

The ability of natural prostaglandins (PGs) and synthetic prostanoids of B, H and E(1)-types to prevent CCl(4)-induced liver injury in vitro was examined. Seven analogs of PGB, 3 derivatives of PGH and two 11-deoxy-analogs of PGE(1) decreased cytotoxic index of CCl(4) by 2-fold and were more effective then such well-known hepatoprotectors as silymarin, curcumin and PGI(2). These prostanoids reduced trien conjugates formation by 25-95% and strongly prevented LDH leakage through plasma membrane. The results from the structure-activity relationship (SAR) analysis can be summarized as follows: (1) the presence of 2-pyridyl at the 15 position of ω-chain plays the main role in cytoprotection for synthetic analogs of PGH; (2) among 11-deoxy-analogs of PGE(1) the most active substances possess the phenyl residue at C-15 connected with C-13 isoxazolin or C-13 isoxazol; (3) C-13 cyclohexylamine or C-15 phenyl groups in ω-chain and metoxy-group in α-chain are important for protective activity of PGB analogs; (4) synthetic analogs of PGB demonstrate more pronounced cytoprotective properties than prostanoids of H and E-types. This information suggests paths for further exploration in the area of hepatoprotection and the design of novel therapeutic agents.

The mechanism of the rat liver cytochrome P4502E1 inhibition by the synthetic prostanoids of A-type.

AIM: The elucidation of mechanism of A-type synthetic prostanoids inhibitory action on microsomal cytochrome P(450)2E1 (CYP2E1) from rat liver activity was carried out. RESULTS: Analogs U-34 and U-26 in a final concentration of 1 x 10(-5)M inhibited CYP2E1 activity by 93% and 46%, respectively; however natural prostaglandins had no effect. These synthetic prostanoids of A-type (5 x 10(-8) to 10(-4)M) inhibited chlorzoxazone hydroxylation in a dose-dependent manner while IC(50)=7.1 x 10(-7)M and 8.0 x 10(-7)M for U-26 and U-34, respectively. The curves of CYP2E1 activity in the presence of different concentrations of chlorzoxazone and varying concentration of prostanoids were hyperbolic. Double-reciprocal plots of these results 1/V=f(1/S) indicated that prostanoids inhibit CYP2E1 through a competitive mechanism with particular effect. CONCLUSION: CYP2E1 is a target for A-type prostanoids, possessing 2-oxo-4-amino-oct-3(E)-enyl in alpha- or omega-chain, which are able to inhibit its action through a competitive mechanism.

Biochemistry of prostaglandins A.

This review considers modern concepts on the structural-functional properties and antiproliferative, antitumor, and antiviral effects of cyclopentenone prostaglandins A and mechanisms underlying their actions. Possible directions of pharmacological application of these compounds and their analogs are discussed.

Synthetic heteroprostanoids of A- and E-types as novel non-comprehensive inhibitors of adenylyl cyclase in rat hepatocytes.

Treatment of rat hepatocyte plasma membranes with five novel synthetic heteroprostanoids of A- and E-types significantly decreased basal activity of adenylyl cyclase. Inhibition of forskolin-stimulated activity of the enzyme was seen as well. The maximal effective concentration for all substances tested was found at approximately 5x10(-6)-1x10(-5) M. The values of half maximal concentration (IC50) for all prostanoids were at the region of 0.7-1.1 microM. Prostanoids belonging to cyclopentenone group A (U-39, U-26) were less active than analogs of 11-deoxy-PGE1 (TA-227, TA-280, and TA-239). The strongest inhibitory effect of adenylyl cyclase activity (more than 3 times) was determined in the presence of prostanoid TA-227 possessing hydrophobic 15-phenyl ring and isoxazol group in omega-chain. The investigation of AC activity in the presence of different concentrations of prostanoids and varying concentrations of Mg x ATP has demonstrated that a non-comprehensive mechanism with particular effect takes place in case of AC inhibition by the heteroprostanoids.