Abstract
In the presence of glutathione (GSH 400 microM), rat hepatocyte homogenates converted 5-hydroperoxyeicosatetraenoic acid (5-HPETE), via the intermediate leukotriene A4, into leukotriene C4 (LTC4) and leukotriene B4 (LTB4); 5-hydroxyeicosatetraenoic acid (5-HETE) was also a prominent product. During a 5-min incubation with 100 microM (13.4 microgram) 5-HPETE, 0.24 ng of LTC4, 15.4 ng of all-trans-LTB4, 4.3 ng of LTB4, and 12.4 micrograms of 5-HETE were formed/mg of protein. In incubations devoid of GSH, 38.6 ng of all-trans-LTB4, 8.8 ng of LTB4, and 2.2 micrograms of 5-HETE were formed/mg of protein, and 3.3 micrograms of intact 5-HPETE could be recovered. The presence of GSH induced a time-dependent rapid depletion of 5-HPETE, paralleled by large increases in the formation of 5-HETE; formation of LTC4 was detected in the presence but not in the absence of GSH. Addition of thiomalic acid (0.1 mM) or penicillamine (0.2 mM), both inhibitors of selenium-dependent GSH peroxidases, increased formation rates of LTC4 by factors of 3 and 2, respectively, whereas the suppressive effects of GSH on the formation of LTB4 were partially reversed. These results suggest that hepatocytes are capable of the simultaneous synthesis of cysteinyl- and dihydroxy-leukotrienes as well as 5-HETE; the availability of the precursor 5-HPETE and the profile of leukotrienes formed are dependent on the GSH concentration and the extent of GSH peroxidase activity.
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|