Alcohol induction of liver nuclear and microsomal CYP2E1-dependent metabolism of xenobiotics. Activations and detoxciations

M.I. DÍAZ GÓMEZ; S.L. FANELLI; A.M.A. DELGADO DE LAYÑO; G.D. CASTRO; J.A. CASTRO

Ciudad de Mendoza

Congreso; VI Congreso Latinoamericano de Mutagénesis, Carcinogénesis y Teratogenesis Ambiental – XIV Congreso Argentino de Toxicología - XXIV Jornadas Interdisciplinarias de Toxicología; 2005

Asociación Toxicológica Argentina y Asociación Latinoamericana de Mutagénesis, Carcinogénesis y Teratogénesis

In previous studies from our laboratory we reported that highly purified liver nuclei are able to metabolize xenobiotics such as carbon tetrachloride, chloroform; ethanol; nifurtimox and dimethylnitrosamine. In the present study evidence is presented that after repetitive alcohol drinking of a Lieber & De Carli diet for 28 days the CYP2E1 activity of both nuclei and microsomes is significantly induced. As a result of this inductive process there is an enhanced liver microsomal metabolism of CCl4, aniline and o-toluidine. The liver nuclear metabolism of aniline or o-toluidine that was null in control rats became significantly increased in the alcohol-induced animals. The one of CCl4 was also induced and the reactive metabolites formed, covalently reacted with nuclear proteins. Present and past results show that both liver nuclear and microsomal CYP2E1 dependent pathways of metabolism are induced by repetitive alcohol drinking. The yield and reactivity of the resulting products may be critical to estimate the relative weight of both pathways in the resulting toxic/carcinogenic response. The presence of CYP2E1 in the immediate neighborhood of DNA, nuclear proteins and lipids may be of significance in the CYP2E1 dependent activation of procarcinogens requiring this cytochrome P450 and generating highly reactive intermediates. Supported by CONICET and UNSAM (PIDA UF016).