Hepatic arachidonic acid metabolism is disrupted after hexachlorobenzene treatment

SILVIA C. BILLI DE CATABBI; ALICIA FALETTI; FEDERICO FUENTES; LEONOR C. SAN MARTÝ´N DE VIALE; ADRIANA C. COCHO´N

TOXICOLOGY AND APPLIED PHARMACOLOGY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2005 vol. 204 p. 187 - 195

0041-008X

AbstractHexaclorobenzene (HCB), one of the most persistent environmental pollutants, can cause a wide range of toxic effects including cancer inanimals, 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 A2 (cPLA2) activity were investigated inan experimental model of porphyria cutanea tarda induced by HCB. Female Wistar rats were treated with a single daily dose of HCB (100 mgkg1 body weight) for 5 days and were sacrificed 3, 10, 17, and 52 days after the last dose. HCB treatment induced the accumulation of hepaticporhyrins 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 thepresence of NADPH, hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs), 11,12-Di HETE, and N-OH/N-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 dosethan at the other time points studied. In addition, HCB treatment markedly enhanced PGE production and release in liver slices. This HCBeffect was time dependent and reached its highest level after 10 days. At this time cPLA2 activity was shown to be increased. Unexpectedly,HCB produced a significant decrease in cPLA2 activity on the 17th and 52nd day. Our results demonstrated for the first time that HCB inducesboth the cyclooxygenase and CYP-dependent AA metabolism. The effects of HCB on AA metabolism were previous to the onset of a markedporphyria and might contribute to different aspects of HCB-induced liver toxicity such as alterations of membrane fluidity and membraneboundprotein function. Observations also suggested that a possible role of cPLA2 in the early increase of AA metabolism cannot be excluded.However, the existence of other pathway(s) for metabolizable AA generation different from cPLA2 activation is also proposed.