Biotransformation enzymes in human intestine: critical low levels in the colon?

Abstract

Biotransformation or drug-metabolising enzymes have an important function in the detoxication of ingested toxic, carcinogenic, or tumour promoting compounds. Enzyme activity and isoenzyme composition of three biotransformation systems: glutathione Stransferase, uridine diphosphate-glucuronosyltransferase, and cytochrome P-450 were studied in normal small and large intestinal mucosa from three kidney donors. The activity of most drug-metabolising enzymes decreases slightly from proximal to distal small intestine, whereas in the mucosa of the large intestine a sharp fall in activity was observed. The isoenzyme composition for each of the three biotransformation systems changed from the small to the large intestine. Class Alpha glutathione S-transferases were not expressed in the colon, in contrast to the small intestine where both Alpha and Pi class isoenzymes are present. In addition, with monoclonal antibodies fewer protein bands for UDP-glucuronosyltransferases and cytochrome P-450 were detected in the colon. In the small intestine both isoforms P-4504 and P-450, were present, whereas in the colon only reduced amounts of cytochrome P-4504 could be visualised. For UDP-glucuronosyltransferase, 53 and 54 kDa proteins could be detected in the small intestine, but in the colon there was only weak staining ofthe 54 kDa band. In the normal human colon enzymes are less active and there are fewer isoenzymes present in the mucosa than in the small intestine. This implies a lower level of the detoxifying potential in the colon, which might be important in regard to the high rates ofcarcinogenesis in the colon.

Glutathione and glutathione S-transferases in Barrett's epithelium

“…Mucosal glutathione S-transferase activity in the different parts of the gastrointestinal tract was plotted against the tumour incidence in the Dutch population (CBS, 1987). Glutathione S-transferase activities in the small intestine (n = 14) are obtained from Table II and Peters et al (1991). Values of esophagus (n = 10) are from Table II, gastric values are from Table II and Peters et al (1990b), and data of colon/rectum (n = 24) are from Peters et al (1992).…”

“…Such a trend seems to be present also for other tissues, since glutathione S-transferase activity is high in liver and kidney (Howie et al, 1990) where tumour incidence is relatively low, at least in the livers from nonhepatitis B infected individuals, whereas glutathione Stransferase activity in lung and breast is low (Howie et al, 1990), and here tumour incidence is high (CBS, 1987). One has to realise however that at sites where glutathione S-transferase activity is low, low expression levels of other biotransformation enzymes may occur, as found for the colon (Peters et al, 1991).…”

“…Biotransformation enzymes, and in particular glutathione S-transferases are present in most epithelial tissues of the human gastrointestinal tract (Peters et al, 1991;Peters et al, 1990b). Their function is protection of the tissue against toxic or carcinogenic compounds, entering the body as food components, food additives or drugs (Peters et al, 1991;Mannervik & Danielson, 1988;Koster et al, 1989).…”

“…Their function is protection of the tissue against toxic or carcinogenic compounds, entering the body as food components, food additives or drugs (Peters et al, 1991;Mannervik & Danielson, 1988;Koster et al, 1989). Such compounds may be metabolised by conjugation with glutathione yielding less harmful and more water soluble molecules, which are then excreted via bile or urine.…”

Glutathione-S-Transferase and GST-π in Gastric Carcinoma

“…Our diet contains many toxic or potentially carcinogenic compounds which are absorbed and metabolized in the gastrointestinal tract (GIT). Metabolization or biotransformation of enzymes such GSTs also occur in the epithelial cells all over the human GIT [17] .…”