Interference of arachidonic acid and its metabolites with TNF-alpha release by ochratoxin A from rat liver.
We investigated the role of arachidonic acid and its metabolites on the ochratoxin A (OTA) provoked release of proinflammatory and apoptotic cytokine TNF-alpha from blood-free perfused rat liver. OTA induced TNF-alpha release dose- and time-dependently yielding 2600 pg TNF-alpha/ml at 2.5 micromol/l after 90 min without significant release of LDH and lactate. Aristolochic acid, 50 micromol/l, a phospholipase A2 inhibitor, and 10 micromol/l of exogenous arachidonic acid decreased TNF-alpha below normal level. Indomethacin, 10 micromol/l, a potent inhibitor of the cyclooxygenase (COX) pathway, almost doubled TNF-alpha concentrations in the perfusion solution to reach 5500 pg/ml at 90 min. On the other hand, inhibition of lipoxgenase (LPX) by 30 micromol/l nordihydroguaiaretic acid (NDGA) and the cytochrome P-450 (CYP) pathway by 100 micromol/l of metyrapone decreased TNF-alpha below normal levels as well. Concurrent administration of two blockers (COX inhibitor with LPX inhibitor, or COX inhibitor with CYP-450 inhibitor, or LPX inhibitor with CYP-450 inhibitor) blocked TNF-alpha release below normal levels. In addition, 10 micromol/l caffeic acid phenylethyl ester, a NF-(kappa)B inhibitor, blocked OTA mediated TNF-alpha release. In conclusion, arachidonic acid and its cyclooxygenase metabolites are suppressors of OTA mediated TNF-alpha release from liver, whereas LPX and CYP-450-metabolites have the opposite effect. OTA-induced TNF-alpha release is likely to occur via the NF-(kappa)B transcription factor pathway in perfused rat liver.
Al-Anati
L
L
Faculty of Veterinary Medicine, Institute of Pharmacology and Toxicology, Fachbereich Veterinarmedizin (FB 10), Justus-Liebig-University Giessen, Frankfurter Street 107, DE-35392 Giessen, Germany.
Katz
N
N
Petzinger
E
E
D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D034341:Aristolochic Acids / Q000494:pharmacology; D002109:Caffeic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009793:Ochratoxins / Q000633:toxicity*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism*
D034341:Aristolochic Acids; D002109:Caffeic Acids; D016328:NF-kappa B; D009793:Ochratoxins; D014409:Tumor Necrosis Factor-alpha; C025589:ochratoxin A; D016718:Arachidonic Acid; C000228:aristolochic acid I; D010741:Phospholipases A; D054467:Phospholipases A2; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol; D007213:Indomethacin