Liver nuclear and microsomal CYP2E1-mediated metabolism of xenobiotics in rats chronically drinking an alcohol-containing liquid diet.
In previous studies from our laboratory, the presence in highly purified liver nuclei of metabolic pathways for processing ethanol (EtOH), N-nitrosodimethylamine (NDMA), carbon tetrachloride and chloroform was reported. All these chemicals are known to be metabolized in liver microsomes, via cytochrome P450 2E1 (CYP2E)-mediated processes. In the present work we checked whether rat liver nuclei from rats chronically drinking an alcohol-containing liquid diet exhibited an enhanced ability to metabolize chemicals known to require CYP2E1 participation for given metabolic transformations. The nicotinamide adenosine dinucleotide phosphate (NADPH)-requiring metabolism of p-nitrophenol to p-nitrocathecol; the activation of carbon tetrachloride to trichloromethyl radicals, covalently binding to proteins; and the ring hydroxylation of aniline and o-toluidine were studied. Comparison of the obtained nuclear activities against the one present in the microsomal counterpart, and their respective response to the EtOH inductive effect after repetitive exposure to it, was studied. The obtained results showed that rat liver nuclei exhibited less p-nitrophenol hydroxylase activity than microsomes, but it was inducible by repetitive alcohol drinking to equivalent levels of those of microsomes from control animals. Nuclei exhibited the ability to activate CCl4, which was significantly enhanced by alcohol drinking. Aniline was ring hydroxylated in liver microsomes but not in nuclei from either control or EtOH-treated animals. In contrast, nuclei and microsomes metabolized o-toluidine to ring hydroxylated products. They are considered less toxic in nature but other authors reported a genotoxic effect for one of them. The production of the ring hydroxylated metabolites was enhanced by repetitive EtOH drinking. Results suggest that nuclear metabolism of xenobiotics might be relevant for either activations or detoxications mediated by CYP2E1 and that repetitive exposure to EtOH might significantly modulate those processes.
Diaz Gómez
Maria I
MI
Centro de Investigaciones Toxicológicas (CEITOX), CITEFA/CONICET J. B. de La Salle 4397, B1603ALO Villa Martelli, Buenos Aires, Argentina.
Fanelli
Silvia L
SL
Delgado de Layño
Aurora M A
AM
Castro
José A
JA
Castro
Gerardo D
GD
D000437:Alcoholism / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology*; D022781:Hepatocytes / Q000201:enzymology; D006900:Hydroxylation / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014052:Toluidines / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism*
D000814:Aniline Compounds; D002492:Central Nervous System Depressants; D014052:Toluidines; D015262:Xenobiotics; D000431:Ethanol; C023622:2-toluidine; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1; C023650:aniline