HEXACHLOROBENZENE (HCB) INDUCED ALTERATIONS OF CYTOCHROME P450 ACTIVITIES ON ARACHIDONIC ACID AND UROPORPHYRINOGEN III

F. FUENTES; S. BILLI; L C. SAN MARTÍN DE VIALE

Villa Carlos Paz, Córdoba, Argentina

Congreso; XXXVII Reunión Anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular (SAIB); 2001

Sociedad Argentina de Investigación Bioquímica y Biología Molecular (SAIB)

A study was made on the effect of HCB induction of isoenzymes of cytochrome P450 (P450) on the P450 dependent metabolism of two endogenous substrates: uroporphyrinogen (UROgen) and arachidonic acid (AA). With this purpose we evaluated: 1) the activity of P450 1A1, 1A2 and 2B, 2) UROgen oxidation rate and UROgen decarboxylase inhibitor formation, 3) AA metabolization after HCB administration to Wistar rats (5 doses of 100 mgkg bw) as a function of time (1, 2, 3 and 8 weeks (w)) after the 1st dose. P450 1A1, 1A2 and 2B isoenzymes were measured using ethoxyresorufin, metoxyresorufin and aminopyrine as substrates. These activities alwais increased after HCB treatment. P450 1A1 peaked on the 2nd w (6 fold) (nv:43-70 pmol/min/mg prot) while the 1A2 and 2B isoforms did so on the 1st w (17 fold (nv:39-60 pmol/min/mg prot) and 8 fold (nv:1,7-2,1 nmol/min/mg prot) respectively). The rate of UROgen oxidation increased at all assayed times (185-300 vs 58-66 pmoles/min/mg prot). The P450 dependent AA metabolization was evaluated using [3H]AA and TLC. Treated rats showed alterations respect to control activities (0,75-1 nmol /min/mg prot) and no activity was detected after 8 w. ωsOH-AA increased on 1-3 w and declined on 8 w, while epoxy-AA always diminished. Thus, P450 1A1, 1A2 and 2B-induction by a foreing drug (HCB) produced alterations of P450 activities on endogenous substrates belonging to different metabolisms: heme pathway and P450 dependent AA metabolism. So, leading to porphyria and decreased production of bioactive lipids.