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 inflammation that have been implicated in certain liver injury models. Inasmuch as GSH is a cofactor for the synthesis of cysteinyl-LTs and since inflammation is a prominent component of ANIT injury, we hypothesized that LTs are involved in producing the hepatic insult that results from ANIT 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 LTB4 in Ca++ ionophore-stimulated whole blood from rats treated with the inhibitors. A63162 attenuated the hepatic parenchymal injury caused by ANIT and resulted in a modest decrease in ANIT-induced cholestasis. In contrast, neither Zileuton nor MK-886 attenuated liver injury. AT-125 (Acivicin) inhibits gamma-glutamyl transferase (GGT), the enzyme that catalyzes the formation of LTD4 from LTC4. AT-125 pretreatment did not prevent ANIT-induced hepatic parenchymal insult. It did, however, ameliorate the cholestasis caused by ANIT. In conclusion, the partial protection afforded by A63162 and AT-125 likely results from effects unrelated to the formation of LTs, since Zileuton and MK-886 inhibited LT synthesis without affording protection. The lack of protection by Zileuton and MK-886 in the face of LT synthesis inhibition suggests that LTs are not necessary for the expression of injury after ANIT administration.
Bailie
M B
MB
Department of Pharmacology/Toxicology, Michigan State University, East Lansing 48824, USA.
Dahm
L J
LJ
Peters-Golden
M
M
Harris
R R
RR
Carter
G W
GW
Roth
R A
RA
D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D000081:Acetamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D006918:Hydroxyurea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000096:biosynthesis / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy; D008297:Male; D010647:Phenyl Ethers; D051381:Rats; D017207:Rats, Sprague-Dawley; D002722:Chlorobenzenes
D015058:1-Naphthylisothiocyanate; D000081:Acetamides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000001:Calcimycin; D005978:Glutathione; D006918:Hydroxyurea; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010647:Phenyl Ethers; C068663:N-hydroxy-N-(1-(4-(phenylmethoxy)phenyl)ethyl)-acetamide; C060893:MK-886; D002722:Chlorobenzenes; C063449:zileuton