Hepatic arachidonic acid metabolism is disrupted after hexachlorobenzene treatment

• Published in: Toxicology and applied pharmacology Vol. 204; no. 2; pp. 187 - 195
• Main Authors: Billi de Catabbi, Silvia C., Faletti, Alicia, Fuentes, Federico, San Martín de Viale, Leonor C., Cochón, Adriana C.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 15-04-2005; Elsevier
• Subjects: Animals; Arachidonic acid; Arachidonic Acid - antagonists & inhibitors; Arachidonic Acid - chemistry; Arachidonic Acid - metabolism; Biological and medical sciences; Cytochrome P-450 CYP1A1 - biosynthesis; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P450; Cytosolic phospholipase A 2; Disease Models, Animal; Female; Hexachlorobenzene; Hexachlorobenzene - administration & dosage; Hexachlorobenzene - adverse effects; Hydroxyeicosatetraenoic Acids - biosynthesis; Intubation, Gastrointestinal; Liver - chemistry; Liver - metabolism; Medical sciences; Methods; Microsomes, Liver - chemistry; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; NADP - metabolism; Oxidoreductases - biosynthesis; Phospholipases A - metabolism; Phospholipases A2; Porphyrias, Hepatic - chemically induced; Prostaglandin; Prostaglandins E - biosynthesis; Rat liver; Rats; Rats, Wistar; Time Factors; Toxicology; AA; EROD; Prostaglandin; Rat liver; HCB; Cytochrome P450; Ah; TCDD; TLC; DAG; Arachidonic acid; COX; cPLA 2; HETE; MAG; Cytosolic phospholipase A 2; EET; PG; APND; CYP; Hexachlorobenzene; MROD; Rat; Digestive system; Enzyme; Arachidonic acid derivatives; Liver; Rodentia; Polyunsaturated fatty acid; Lipids; Esterases; Metabolism; Phospholipase A; Cytosolic phospholipase A2; Carboxylic ester hydrolases; Vertebrata; Mammalia; Treatment; Eicosanoid; Animal; Hydrolases
• DOI: 10.1016/j.taap.2004.09.001
• EISSN: 1096-0333
• ISSN: 0041-008X

Hexaclorobenzene (HCB), one of the most persistent environmental pollutants, can cause a wide range of toxic effects including cancer in animals, and hepatotoxicity and porphyria both in humans and animals. In the present study, liver microsomal cytochrome
P450 (CYP)-dependent arachidonic acid (AA) metabolism, hepatic PGE production, and cytosolic phospholipase A
2 (cPLA
2) activity were investigated in an experimental model of porphyria cutanea tarda induced by HCB. Female Wistar rats were treated with a single daily dose of HCB (100 mg kg
−1 body weight) for 5 days and were sacrificed 3, 10, 17, and 52 days after the last dose. HCB treatment induced the accumulation of hepatic porhyrins from day 17 and increased the activities of liver ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), and aminopyrine N-demethylase (APND) from day 3 after the last dose. Liver microsomes from control and HCB-treated rats generated, in the presence of NADPH, hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs), 11,12-Di HETE, and ω-OH/ω-1-OH AA. HCB treatment caused an increase in total NADPH CYP-dependent AA metabolism, with a higher response at 3 days after the last HCB dose than at the other time points studied. In addition, HCB treatment markedly enhanced PGE production and release in liver slices. This HCB effect was time dependent and reached its highest level after 10 days. At this time cPLA
2 activity was shown to be increased. Unexpectedly, HCB produced a significant decrease in cPLA
2 activity on the 17th and 52nd day. Our results demonstrated for the first time that HCB induces both the cyclooxygenase and CYP-dependent AA metabolism. The effects of HCB on AA metabolism were previous to the onset of a marked porphyria and might contribute to different aspects of HCB-induced liver toxicity such as alterations of membrane fluidity and membrane-bound protein function. Observations also suggested that a possible role of cPLA
2 in the early increase of AA metabolism cannot be excluded. However, the existence of other pathway(s) for metabolizable AA generation different from cPLA
2 activation is also proposed.