COMPARATIVE ACTIVITIES OF XENOBIOTIC METABOLIZING ENZYMES IN SHEEP LIVER AND SMALL INTESTINAL MUCOSA

MATÉ L.; VIRKEL G.; LIFSCHITZ A.; SALLOVITZ J.; BALLENT M.; LANUSSE C.

Tandil

Congreso; XL reunión anual de la Asociación Argentina de Farmacología Experimental; 2008

SAFE

The intestinal mucosa has the ability to metabolize a great number of xenobiotics by both phase 1 and phase 2 reactions. The objective of this work was to evaluate xenobiotic metabolizing enzyme activities in cytosolic and microsomal fractions obtained from sheep liver and small intestinal mucosa (duodenum, jejunum and ileum). Oxidative (cytochrome P450-dependent), reductive (carbonyl reductase) and conjugative enzyme activities were measured using known marker substrates. The metabolic activities measured in liver subcellular fractions were used as reference values. Intestinal N-demethylase P450-dependent activities were 11.0 - 46.1 % (P450 3A) and 3.0 - 7.1 % (P450 2C) than those measured in the liver. These metabolic activities did not decrease nor increase along the small intestine. Conversely, microsomal O-deethylase P450-dependent  activities (CYP 1A) were not detected in sheep small intestinal mucosa. Intestinal carbonyl reductase activities resulted 14.3 – 23.4 % (microsomes) and 18.7 – 33.1 % (cytosol) than those measured in the liver. Intestinal microsomes were able to conjugate 1-naphthol, (an UGT-mediated reaction) and 1-cloro,2,4-dinitrobenzene (a GST probe). Metabolic reactions taking place in the intestinal mucosa may contribute to the pre-systemic metabolism of orally administered drugs. These results are a further contribution to the knowledge of the extra-hepatic biotransformation pathways in ruminants.