LEUKOTRIENES AND ALPHA-NAPHTHYLISOTHIOCYANATE-INDUCED LIVER-INJURY

alpha-Naphthylisothiocyanate (ANIT) administration to rats results in periportal hepatic inflammation and injury. Glutathione (GSH) appears to be necessary for the liver injury to occur. The leukotrienes (LTs) are metabolites of arachidonic acid and potent mediators of inflammati on that have been implicated in certain liver injury models. Inasmuch as GSH is a cofactor for the synthesis of cysteinyl-LTs and since infl ammation is a prominent component of ANIT injury, we hypothesized that LTs are involved in producing the hepatic insult that results from AN IT administration. To test this hypothesis, rats were treated with one of several inhibitors of LT biosynthesis, A63162, Zileuton or MK-886. Each of these agents prevented the formation of LTB(4) in Ca++ ionoph ore-stimulated whole blood from rats treated with the inhibitors, A631 62 attenuated the hepatic parenchymal injury caused by ANIT and result ed in a modest decrease in ANIT-induced cholestasis. In contrast, neit her Zileuton nor MK-886 attenuated liver injury. AT-125 (Acivicin) inh ibits gamma-glutamyl transferase (GGT), the enzyme that catalyzes the formation of LTD(4) from LTC(4). AT-125 pretreatment did not prevent A NIT-induced hepatic parenchymal insult. It did, however, ameliorate th e cholestasis caused by ANIT. In conclusion, the partial protection af forded by A63162 and AT-125 likely results from effects unrelated to t he formation of LTs, since Zileuton and MK-886 inhibited LT synthesis without affording protection, The lack of protection by Zileuton and M K-886 in the face of LT synthesis inhibition suggests that LTs are not necessary for the expression of injury after ANIT administration.