Prevention by inhibitors of arachidonic acid cascade of liver carcinogenesis, cirrhosis and oxidative DNA damage caused by a choline-deficient, L-amino acid-defined diet in rats.
Effects of inhibitors of arachidonic acid (AA) cascade on the development of fatty liver, cirrhosis, glutathione S-transferase placental form (GST-P)-positive preneoplastic nodules, neoplastic nodules and generation of 8-hydroxydeoxyguanosine (8-OHdG), caused by a choline-deficient, L-amino acid-defined (CDAA) diet, were examined in Fischer 344 male rats by feeding CDAA diet supplemented with the inhibitors for 12 and 30 weeks. None of the inhibitors affected fatty liver. Among cyclooxygenase (COX) inhibitors, an irreversibly acting acetylsalicylic acid and a long-acting piroxicam, and to a much lesser extent the short-acting ibuprofen but not indomethacin, inhibited the development of cirrhosis, GST-P-positive and neoplastic nodules and generation of 8-OHdG. A phospholipase A2 inhibitor p-bromophenacylbromide (BPB) also exerted similar but lesser extent of inhibitory effects. Lipoxygenase inhibitors quercetin and nordihydroguiaretic acid inhibited GST-P-positive nodules but not cirrhosis or 8-OHdG. Present results suggest that perturbed AA cascade, particularly augmented COX pathway, might play key roles in the causation of liver lesions in the CDAA diet model.
Department of Oncological Pathology, Cancer Center, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634, Japan.
A
A
Denda
T
T
Endoh
Q
Q
Tang
T
T
Tsujiuchi
D
D
Nakae
Y
Y
Konishi
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000596:Amino Acids / Q000008:administration & dosage; D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors*; D001835:Body Weight; D002796:Choline Deficiency / Q000150:complications*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005247:Feeding Behavior; D005982:Glutathione Transferase / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008106:Liver Cirrhosis, Experimental / Q000473:pathology / Q000517:prevention & control*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D018384:Oxidative Stress; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D051381:Rats; D011916:Rats, Inbred F344
D000596:Amino Acids; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D000080242:8-Hydroxy-2'-Deoxyguanosine; D005982:Glutathione Transferase; D010741:Phospholipases A; D054467:Phospholipases A2; D003849:Deoxyguanosine