Hepatotoxic Agent Thioacetamide Induces Biochemical and Histological Alterations in Rat Small Intestine

We have assessed the effect of the oral ingestion of thioacetamide on small intestine structure and function. Thioacetamide-treated rats showed diminished mucosa weight; protein, DNA, and RNA content; and leucine aminopeptidase activity as compared to controls in both jejunum and ileum. In the jejunum, there was a reduction in the activities of alkaline phosphatase, ATPase, glucose-6-phosphatase, and myeloperoxidase, whereas in the ileum, maltase, lactase, and -glutamyltranspeptidase were reduced. In both jejunum and ileum we found enlarged intercellular spaces, dark epithelial enterocytes, and lymphocyte infiltration. Enterocytes showed lobulated nuclei, deranged mitochondria with loss of their cristae, dilated rough endoplasmic reticulum containing dense material, and vesiculation of the smooth endoplasmic reticulum and the Golgi apparatus. Smooth muscle cells of the intestine exhibited ultrastructural alterations. These findings indicate that chronic oral intake of thioacetamide mimics not only hepatic alterations but also small intestine alterations normally associated with human cirrhosis.     

Does Senna Extract Promote Growth of Aberrant Crypt Foci and Malignant Tumors in Rat Colon?

Current evidence suggests that aberrant cryptfoci (ACF) can be used to evaluate agents for theirpotential colon carcinogenic activity. The aim of thepresent study was to determine whether senna pod extract (SE) itself induces ACF and tumors in the ratcolon or increases the development of ACF and tumorsinduced by azoxymethane (AOM). A daily administration ofSE 10 mg/kg by mouth for 13-28 weeks produced a weak laxative effect but did not itself causethe appearance of ACF or tumors. The numbers of ACF andtumors induced by AOM were, however, increased by a doseof SE (100 mg/kg) able to induce chronic diarrhea over three months. These resultssuggest that SE does not cause the appearance of ACF ortumors in the rat colon nor does it have a promotingeffect when given to rats at a dose that produceslaxation (10 mg/kg), whereas a diarrhogenic dose (100mg/kg) increases the appearance of tumors induced byAOM.     

Recombinant or Plasma-Derived Antisecretory Factor Inhibits Cholera Toxin-Induced Increase in Evans Blue Permeation of Rat Intestinal Capillaries

The effect of cholera toxin on small intestinalcapillary function, utilizing the Evans blue dye method,was analyzed. The modulatory influence of plasma-derivedor recombinant human antisecretory factor on this variable was also investigated. MaleSprague-Dawley rats were briefly anesthetized withether, and a jejunal loop was constructed that waschallenged for 90 min with phosphate-buffered saline or cholera toxin. Five minutes prior to death, therats received an intravenous injection of Evans blue.The tissue content of dye in the loop was quantitatedspectrophotometrically or demonstrated histochemically. Cholera toxin increased the recovery of Evansblue; extravasation of the dye was prominent in the topof the villi, while the crypts were spared. It issuggested that the toxin caused increased transcapillary permeation of albumin in a heterogenous fashionin the gut wall. This effect of the toxin was preventedby pretreatment with the antisecretory factor.     

Effects of Tolcapone, a Catechol-O-Methyltransferase Inhibitor, and Sinemet on Intestinal Electrolyte and Fluid Transport in Conscious Dogs

Tolcapone (T) is a novelcatechol-O-methyltransferase (COMT) inhibitor recentlyintroduced for the treatment of Parkinson's disease. Inclinical efficacy studies, T has been associated with alow incidence of diarrhea. The objectives of the study wereto examine whether T and its adjunctive drug Sinemet (S)could influence intestinal fluid and electrolytetransport as a possible cause for the diarrhea. The studies were conducted in conscious dogssurgically prepared with Thiry-Vella loops constructedfrom a 40-cm jejunal segment. A physiologically bufferedtest solution was perfused into the orad stoma and collected from the caudad stoma. Secretionswere collected at 15-min intervals and analyzed forvolume, electrolytes, lipid phosphorus, and protein. Theacute oral administration of T (10 and 30 mg/kg doses) was well tolerated. Concurrent acuteadministration of S (25 mg/kg) with T (30 mg/kg) wasalso well tolerated. The acute oral administration of Tinduced a dose-dependent efflux of intestinal fluid and electrolytes (sodium, potassium, chloride, andbicarbonate) secretion (P < 0.05). The oralcoadministration of S (25 mg/kg) with T (30 mg/kg)accelerated the onset of the stimulation of intestinalsecretion. Despite the significant stimulation ofintestinal secretion, none of the dogs developeddiarrhea, indicating the importance of intestinalcompensatory mechanisms. Neither T nor T&S affectedcalcium, lipid, or protein efflux rates, suggesting thatthe stimulated secretion was not a consequence ofintestinal mucosal injury. The chronic (seven-day)administration of T and T&S was associated withreduced intestinal secretory responses when comparedwith the acute administration of the same drugs; Senhanced the T-induced tolerance development. The basisfor such tolerance is unknown. In conclusion, the stimulatory systemic actions of tolcapone onintestinal secretion may, under certain conditions,contribute to the induction of diarrhea in susceptiblepatients.     

Inhibition of DNA Synthesis in Caco-2 Cells by Oxidative Stress (Amelioration by Epidermal Growth Factor)

The role of oxidative stress in the regulationof intestinal epithelial proliferation was examined byevaluating the effect of H₂O₂andxanthine oxidase + xanthine (XO + X) on[³H]thymidine incorporation into DNA in Caco-2 cells. DNAsynthesis was highest 4 and 5 days after seeding, whileit declined rapidly between 5 and 12 days. Pretreatmentfor 0.5-24 h with H₂O₂or XO + X reduced DNA synthesis on 4- to6-day-old, but not on 7- to 20-day-old cells. The effectof XO + X on DNA synthesis was significantly reduced bycatalase, superoxide dismutase, and ferric chloride, but pretreatment with deferoxamine potentiatedXO + X-induced inhibition of DNA synthesis.Coadministration of epidermal growth factor (EGF) for 24hr reduced the H₂O₂and XO +X-induced inhibition of DNA synthesis; this effect of EGFwas not observed up to 8 hr. Results show thatO_2-and H₂O₂rapidlyinhibit DNA synthesis in Caco-2 cells and that EGFrestores DNA synthesis in oxidant-treatedcells.     

Indomethacin and Pancreatic Enzymes Synergistically Damage Intestine of Rats

The use of high-dose pancreatic enzymes bypatients with cystic fibrosis was associated with thedevelopment of fibrosing colonopathy. Preliminarystudies indicated that the infusion of high-dosepancreatic enzymes alone did not cause intestinal damage.We hypothesized that cystic fibrosis patients thatdeveloped fibrosing colonopathy had increased intestinalpermeability. Our goal was to develop a rat model for pancreatic enzyme-induced fibrosingcolonopathy by increasing intestinal permeability withthe use of indomethacin. Pancreatic enzymes, 150,000units/kg/day, and indomethacin, 3 mg/kg/day, alone and in combination were administered via duodenalcatheter to rats for 10 days. Indomethacin andpancreatic enzymes caused intestinal damage, resultingin significant increases in the total number of ulcers (P < 0.007), the number of severe ulcers (P< 0.003), and ulcers in the cecum and colon (P <0.0007). We conclude that the combination ofindomethacin and pancreatic enzymes acts synergistically to cause damage to the intestine.