Sulfide-detoxifying enzymes in the human colon are decreased in cancer and upregulated in differentiation

Abstract

Ramasamy, S., S. Singh, P. Taniere, M. J. S. Langman, and M. C. Eggo. Sulfide-detoxifying enzymes in the human colon are decreased in cancer and upregulated in differentiation. Am J Physiol Gastrointest Liver Physiol 291: G288 -G296, 2006. First published February 23, 2006 doi:10.1152/ajpgi.00324.2005.-H 2S is highly toxic and selectively inhibits butyrate oxidation in colonocytes. Ineffective detoxification may result in mucosal insult, inflammation, and ultimately in colorectal cancer (CRC). Rhodanese can detoxify H 2S and is comprised of two isoenzymes: thiosulfate sulfurtransferase (TST) and mercaptopyruvate sulfurtransferase (MST). Using specific antisera to discriminate TST from MST, we found that only TST could detoxify H2S. In sections of normal colon, both enzymes were located on the luminal mucosal surface, and they were expressed in the colonocytes but not in the mucin-secreting goblet cells. Expression of both enzymes was focally lost in ulcerative colitis and markedly reduced in advanced colon cancer, the disease progression correlating with the decreased expression of MST and TST. In HT-29 cells, a human colon cancer cell line, TST activity and expression were significantly increased by butyrate and by histone deacetylase inhibition, agents that promote HT-29 cell differentiation. Sulfide (0.1 mM) also increased TST activity, but higher sulfide concentrations (0.3-3 mM) were toxic. Preincubation in butyrate to increase TST expression, decreased sensitivity of the cells to sulfide toxicity. We conclude that decreased expression of TST (or MST) is a tumor marker for CRC. TST expression is increased in colonocyte differentiation. Dysregulation of TST expression and activity resulting in inability to effectively detoxify could be a factor in the cell loss and inflammation that accompany ulcerative colitis and ultimately then in CRC. colorectal cancer; thiosulfate sulfurtransferase; butyrate; HT-29 IN THE HUMAN COLON, anaerobic bacteria produce hydrogen sulfide (H 2 S) (25), which inhibits the oxidation of short-chain fatty acids (SCFA) (18,19). SCFAs are the main energy source (Ͼ70% ) for colonocytes (18) and also contribute 5-10% of the total energy supplies in humans. Inhibition of their oxidation in the colon will result in colonocyte starvation and death, resulting in inflammation. This, the "energy deficiency" hypothesis of Roediger (18), is postulated to lead to ulcerative colitis (UC). Many studies have shown that patients with UC have increased colorectal cancer (CRC) risk, with Prior et al. (16) estimating this as an 11-fold excess. On the basis of these studies, we suggest that the expression of enzymes important in sulfide detoxification is essential to preserve a healthy mucosa and that derangements in expression may accompany UC and CRC.We recently showed that colonic mucosal rhodanese can detoxify hydrogen sulfide (15) and thus might protect against mucosal injury. Rhodanese is a mitochondrial enzyme, present in all living organisms from bacteria to humans, and is thought to play a cen...

Taurocholic acid metabolism by gut microbes and colon cancer

“…Loss of sulfide-detoxification has been reported to occur in active UC and CRC. 113 Such a situation is conducive to genotoxicity leading to genetic changes and CRC.…”

Sulfate-reducing bacteria of the human intestine. II. The role in the diseases development

“…Збіль-шену кількість останніх часто виявляють у людей із ревматичними захворювання-ми, з анкілозуючим спондилітом тощо [20]. Припускають також, що сульфатвіднов-лювальні бактерії (СВБ) можуть бути причиною деяких форм раку прямої кишки через утворення гідроген сульфіду [6,85], який негативно впливає на метаболізм клітин кишечника і спричиняє виникнення різноманітних захворювань [79,92].…”

“…Як уже згадувалося, гідроген сульфід може спричиняти пошкодження ДНК, а, отже, бути мутагеном [6,9,85,100]. H 2 S у концентрації 1 мкмоль/л пошкоджує ДНК ізольованих ядер, виділених із клітин яєчника китайського хом'ячка [6].…”

“…Роданеза має дві ізоформи: тіосульфатсульфуртрансфераза (TST) і меркаптопіруватсульфуртрансфераза (MST). TST нейтралізує гідроген сульфід у колоноцитах [85,92]. Експресія обох ізоферментів (MST і TST) знижується за ви-разкового коліту і раку товстої кишки, порівняно з нормальною слизовою, що обу-мовлює можливий розвиток хвороби.…”

“…Утворення бутира-ту у сліпій і товстій кишках збільшує активність TST [43,85]. Виразковий коліт ви-никає переважно у лівій частині товстої кишки.…”