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

• Published in: Prostaglandins & other lipid mediators 2009-06, Vol.89 (1-2), p.16-19
• Main Authors: Hubich, A I, Lakhvich, F A, Sholukh, M V
• Format: Article
• Language: English
• Subjects: Animals; Cytochrome P-450 CYP2E1 Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; In Vitro Techniques; Kinetics; Liver - cytology; Liver - enzymology; Microsomes - enzymology; Prostaglandins - chemical synthesis; Prostaglandins - chemistry; Prostaglandins - pharmacology; Rats
• ISSN: 1098-8823
• DOI: 10.1016/j.prostaglandins.2009.02.003

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. 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. 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.