Biotransformation of xenobiotics in the human colon and rectum and its association with colorectal cancer

Abstract

In humans, the liver is generally considered to be the major organ contributing to drug metabolism, but studies during the last years have suggested an important role of the extra-hepatic drug metabolism. The gastrointestinal tract (GI-tract) is the major path of entry for a wide variety of compounds including food, and orally administered drugs, but also compounds - with neither nutrient nor other functional value - such as carcinogens. These compounds are metabolized by a large number of enzymes, including the cytochrome P450 (CYP), the glutathione S-transferase (GST) family, the uridine 5'-diphospho- glucuronosyltransferase (UDP-glucuronosyltransferase - UGT) superfamily, alcohol-metabolizing enzymes, sulfotransferases, etc. These enzymes can either inactivate carcinogens or, in some cases, generate reactive species with higher reactivity compared to the original compound. Most data in this field of research originate from animal or in vitro studies, wherein human studies are limited. Here, we review the human studies, in particular the studies on the phenotypic expression of these enzymes in the colon and rectum to get an impression of the actual enzyme levels in this primary organ of exposure. The aim of this review is to give a summary of currently available data on the relation between the CYP, the GST and the UGT biotransformation system and colorectal cancer obtained from clinical and epidemiological studies in humans.

N-Monosubstituted Methoxy-oligo(ethylene glycol) Carbamate Ester Prodrugs of Resveratrol

“…Scheme 3. Kinetic scheme for stepwise hydrolysis of triprotected (III) derivatives 2-4 to resveratrol (1). II and I represent, each, the two possible isomeric derivatives resulting from hydrolysis of one (II) and two (I) carbamoyl linkages, respectively.…”

“…99% yield as a colourless oil. 1 Triphenylphosphine (10.88 g, 41.5 mmol, 1.25 eq.) in anhydrous THF (25 mL) was added dropwise to a solution of methoxy-oligo(ethylene glycol)-azide (2b-4b) (33.0 mmol, 1.0 eq.)…”

“…84% yield as a pale yellow oil. 1 A solution of resveratrol (0.24 g, 1.1 mmol, 1.0 eq.) and DMAP (0.52 g, 4.2 mmol, 4.0 eq.)…”

“…Evolution has endowed organisms with a powerful apparatus designed to detoxify "xenobiotic" substances which reach the cytoplasm [1][2][3]. These compounds tend to be hydrophobic/apolar to pass the cell membrane.…”

Olive oil prevents benzo(a)pyrene [B(a)P]-induced colon carcinogenesis through altered B(a)P metabolism and decreased oxidative damage in ApcMin mouse model

“…As the carcinogen-induced tumors in the gastrointestinal tract are inextricably linked to the expression of drug metabolizing enzymes [52], pharmacological intervention strategies target these enzymes to assess the magnitude of induction or inhibition by carcinogens in the presence or absence of chemopreventive agents [53]. Towards this end, we investigated how olive oil modulates the metabolism of B(a)P by analyzing the cytochrome P450 biotransformation enzyme expression.…”