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J L Orchard

Publications and source records attributed to J L Orchard.

At least 19 recordsLinked to original sources
PubMed1999

Gender related differences in ATP-dependent transport of dinitrophenyl-glutathione conjugate across murine canalicular liver plasma membrane.

The present study reports gender related differences in ATP-dependent transport of dinitrophenyl-glutathione (GSH) conjugate (DNP-SG), a model GSH xenobiotic conjugate, across murine canalicular liver plasma membrane (cLPM). ATP-dependent transport of DNP-SG across female A/J mouse cLPM was mediated by two components, a high-affinity and a low-affinity component, with corresponding Km of 18 microM (Vmax 0.02 nmol/min.mg) and 500 microM (Vmax 0.23 nmol/min.mg), respectively. On the other hand, only one component for the ATP-dependent transport of DNP-SG was observed in male mouse cLPM (K(m) 130 microM; Vmax 0.18 nmol/min.mg). Moreover, the rate of ATP-dependent transport of DNP-SG was markedly higher in the cLPM fraction of male mouse compared with that of the female. Presence of two transport components in female mouse cLPM, but only one system in the cLPM fraction of male mouse, was confirmed by measuring DNP-SG mediated stimulation of ATP hydrolysis (DNP-SG ATPase activity). To the best of our knowledge, the present study is the first report on gender related differences in ATP-dependent murine canalicular transport of GSH conjugates.

Adenosine Triphosphate↗
PubMed1998

Gender-related differences in susceptibility of A/J mouse to benzo[a]pyrene-induced pulmonary and forestomach tumorigenesis.

Benzo[a]pyrene (BP) is a suspected human carcinogen and is known to produce tumors in the lung and forestomach of mice. Glutathione (GSH) S-transferases (GST) play a major role in the detoxification of the ultimate carcinogen of BP, (+)-anti-7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene ((+)-anti-BPDE). Previous studies have shown gender-related differences in the expression of GST isoenzymes in mice. The present study was designed to test the hypothesis whether gender-related differences in the expression of GST isoenzymes can affect the susceptibility of mice to BP-induced lung and forestomach tumorigenesis. The expression of pi class isoenzyme mGSTP1-1, which is highly efficient in the detoxification of (+)-anti-BPDE, was approximately 3.0- and 1.5-fold higher in the liver and forestomach of male A/J mouse, respectively, as compared with the female. The levels of other major GST isoenzymes, mGSTA3-3 (alpha class), mGSTM1-1 (mu class) and mGSTA4-4 (alpha class), were also significantly higher in the liver of the male mouse as compared with the female. While pulmonary mGSTP1-1 expression did not differ significantly between male and female A/J mice, the expression of mGSTA3-3, mGSTM1-1 and mGSTA4-4 was significantly higher (1.4-4.0-fold) in the lung of the male A/J mouse as compared with the female. At lower concentrations of BP (0.5 mg BP/mouse), the tumor incidence/multiplicity was significantly higher in the lung as well as in the forestomach of female mice as compared with male mice. For example, while 30% of the female mice developed pulmonary tumors 26 weeks after the first 0.5 mg BP administration, none of the male mice had tumors in their lungs. At higher doses of BP (1.5 mg BP/mouse), however, this differential was either abolished or relatively less pronounced. Our results suggest that up to a certain threshold of BP exposure the levels of GST isoenzymes may be an important determinant of susceptibility to BP-induced tumorigenesis in mice.

Animals↗
PubMed1998

ATP-dependent transport of glutathione conjugate of 7beta, 8alpha-dihydroxy-9alpha,10alpha-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene in murine hepatic canalicular plasma membrane vesicles.

Glutathione (GSH) S-transferases (GSTs) have an important role in the detoxification of (+)-anti-7,8-dihydroxy-9,10-oxy-7,8,9, 10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE], which is the ultimate carcinogen of benzo[a]pyrene. However, the fate and/or biological activity of the GSH conjugate of (+)-anti-BPDE [(-)-anti-BPD-SG] is not known. We now report that (-)-anti-BPD-SG is a competitive inhibitor (Ki 19 microM) of Pi-class isoenzyme mGSTP1-1, which among murine hepatic GSTs is most efficient in the GSH conjugation of (+)-anti-BPDE. Thus the inhibition of mGSTP1-1 activity by (-)-anti-BPD-SG might interfere with the GST-catalysed GSH conjugation of (+)-anti-BPDE unless one or more mechanisms exist for the removal of the conjugate. The results of the present study indicate that (-)-anti-BPD-SG is transported across canalicular liver plasma membrane (cLPM) in an ATP-dependent manner. The ATP-dependent transport of (-)-anti-[3H]BPD-SG followed Michaelis-Menten kinetics (Km 46 microM). The ATP dependence of the (-)-anti-BPD-SG transport was confirmed by measuring the stimulation of ATP hydrolysis (ATPase activity) by the conjugate in the presence of cLPM protein, which also followed Michaelis-Menten kinetics. In contrast, a kinetic analysis of ATP-dependent uptake of the model conjugate S-[3H](2,4-dinitrophenyl)-glutathione ([3H]DNP-SG) revealed the presence of a high-affinity and a low-affinity transport system in mouse cLPM, with apparent Km values of 18 and 500 microM respectively. The ATP-dependent transport of (-)-anti-BPD-SG was inhibited competitively by DNP-SG (Ki 1.65 microM). Likewise, (-)-anti-BPD-SG was found to be a potent competitive inhibitor of the high-affinity component of DNP-SG transport (Ki 6.3 microM). Our results suggest that GST-catalysed conjugation of (+)-anti-BPDE with GSH, coupled with ATP-dependent transport of the resultant conjugate across cLPM, might be the ultimate detoxification pathway for this carcinogen.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1998

Differential induction of NAD(P)H:quinone oxidoreductase by anti-carcinogenic organosulfides from garlic.

This study was undertaken to elucidate the mechanism of organ specificity and differential efficacy of garlic organosulfides (OSCs) [diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), dipropyl sulfide (DPS) and dipropyl disulfide (DPDS)] in preventing benzo(a)pyrene (BP)-induced tumorigenesis in mice. The results of the present study reveal a good correlation between chemopreventive efficacies of garlic OSCs and their inductive effects on the expression of NAD(P)H:quinone oxidoreductase (NQO), an enzyme implicated in the detoxification of activated quinone metabolites of BP. Treatment of mice with DADS and DATS, which are potent inhibitors of BP-induced forestomach tumorigenesis, resulted in a statistically significant increase (2.4- and 1.5-fold, respectively) in forestomach NQO activity. In addition, DADS and DATS were much more potent inducers of forestomach NQO activity than DAS, which is a weak inhibitor of BP-induced forestomach tumorigenesis than the former compounds. Propyl-group containing OSCs (DPS and DPDS), which do not inhibit BP-induced tumorigenesis, did not affect forestomach NQO activity. Similar to forestomach, a good correlation was also observed between effects of these OSCs against BP-induced pulmonary tumorigenesis and their effects on NQO expression in the lung. For example, treatment of mice with DAS, which is a potent inhibitor of BP-induced pulmonary tumorigenesis, resulted in about 3.2-fold increase in pulmonary NQO activity. On the other hand, this activity was increased by about 1.5-fold upon DATS administration, which does not inhibit BP-induced cancer of the lung. In conclusion, our results suggest that induction of NQO may be important in anti-cancer effects of garlic OSCs.

Allyl Compounds↗
PubMed1998

Mechanism of inhibition of benzo[a]pyrene-induced forestomach cancer in mice by dietary curcumin.

Curcumin (diferuloylmethane), the major yellow pigment in turmeric, has been shown to inhibit benzo[a]pyrene (BaP)-induced forestomach cancer in mice through mechanism(s) not fully understood. It is well known that while cytochrome P4501A1 (CYP1A1) and epoxide hydrolase (EH) are important in the conversion of BaP to its activated form, (+)-anti-7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BaPDE], the detoxification of (+)-anti-BaPDE is accomplished by glutathione (GSH) S-transferases (GST). Therefore, it seems reasonable to postulate that curcumin may exert anti-carcinogenic activity either by inhibiting activation of BaP or (and) by enhancing the detoxification of (+)-anti-BaPDE. Administration p.o. of 2% curcumin in the diet to female A/J mice for 14 days, which has been shown to cause a significant inhibition in BaP-induced forestomach tumorigenesis, resulted in a modest but statistically significant reduction in hepatic ethoxyresorufin O-deethylase (EROD) activity, a reaction preferentially catalyzed by CYP1A1. While EROD activity could not be detected in the forestomach of either control or treated mice, curcumin feeding caused a statistically significant increase (approximately 2.3-fold) in hepatic EH and GST activities. Hepatic and forestomach GSH levels, and forestomach EH and GST activities were not affected by curcumin treatment. Even though the levels of various hepatic GST isoenzymes were significantly increased upon curcumin feeding, maximum induction was noticed for the pi class isoenzyme (mGSTP1-1), which among murine hepatic GSTs is highly efficient in the detoxification of (+)-anti-BaPDE. In conclusion, the results of the present study suggest that curcumin may inhibit BaP-induced forestomach cancer in mice by affecting both activation as well as inactivation pathways of BaP metabolism in the liver.

Animals↗
PubMed1995

Upper gastrointestinal tract bleeding in institutionalized mentally retarded adults. Primary role of esophagitis.

BACKGROUND: Upper gastrointestinal (UGI) tract bleeding is a common reason for hospitalization of mentally retarded adults. The purpose of this study was to determine the frequency and cause of and risk factors for UGI tract bleeding in institutionalized mentally retarded adults admitted to our hospital. METHODS: Case-control study, with a retrospective review of medical records. SETTING: Inner-city tertiary care hospital. PATIENTS: Mentally retarded adults who reside in one of three long-term care facilities. MEASUREMENTS: Data on demographic features, clinical features, and concurrent medical conditions were collected on mentally retarded adults admitted to our hospital for UGI tract bleeding (n = 40). Data from these patients were compared with those from a control group of mentally retarded adults admitted for nonbleeding conditions (n = 124). Endoscopic data were reviewed on the patients who bled to further clarify the causes of UGI tract bleeding. The patients who bled were compared with those who did not bleed using the chi 2 and Mann-Whitney rank sum tests. RESULTS: Upper gastrointestinal tract bleeding was the most common reason for hospitalization in this patient population. Such bleeding was most commonly caused by erosive esophagitis (70% of patients who bled). Conditions associated with an increased risk for UGI tract bleeding were hiatal hernia, reduced activity, incontinence, hypoalbuminemia, kyphoscoliosis, and spastic quadriplegia. CONCLUSIONS: Upper gastrointestinal tract bleeding is a common cause of hospitalization in mentally retarded adults and is usually due to erosive esophagitis. It is hoped that vigorous efforts to treat gastroesophageal reflux disease may reduce hospitalization in these patients.

Adult↗
PubMed1995

Bacterial esophagitis associated with CD4+ T-lymphocytopenia without HIV infection. Possible role of corticosteroid treatment.

Although infectious esophagitis is usually due to infection with Candida, herpes virus, or cytomegalovirus, bacterial esophagitis is occasionally observed. Recently, patients have been reported with CD4+ T-lymphocytopenia without HIV infection. Bacterial esophagitis per se has not been reported in these patients. We report the case of an 80-year-old patient admitted with a COPD exacerbation after being on chronic steroids. The patient developed esophageal symptoms and was found to have bacterial esophagitis by biopsy. Her CD4+ counts were found to be low, but she denied HIV risk factors and HIV testing was negative. Her CD4+ counts rose into the normal range as her steroids were tapered, and her esophagitis improved on antibiotics. This case is reported to alert physicians to the possible association of bacterial esophagitis with CD4+ T-lymphocytopenia without HIV infection and to discuss the possible etiological role of corticosteroid treatment.

Aged↗
PubMed1993

Different effects of hyperstimulation by similar classes of secretagogues on the exocrine pancreas.

Cholecystokinin and its analogues such as cerulein, muscarinic cholinergic agonists, and gastrin-releasing peptide (bombesin) bind to distinct receptors on the surface of pancreatic acinar cells and stimulate digestive protein secretion by a calcium-dependent mechanism. The mechanisms of the calcium-dependent secretagogue classes has been assumed to be similar. In this study we have noted that dispersed pancreatic acini secrete comparable maximal rates of amylase in response to cerulein and bombesin; however, the maximal level of phosphatidylinositol 4,5-bisphosphate hydrolysis was less with bombesin than with cerulein. The high agonist dose-inhibited secretion in vitro observed with cerulein was absent with bombesin. In vivo administration of supramaximal secretory stimulating doses of both cerulein and bombesin caused pancreatic edema; however, the increase in serum concentrations of amylase and lipase induced by cerulein treatment was not detected with bombesin. These data indicate that cerulein and bombesin display distinctly different effects on the exocrine pancreas both in vivo and in vitro. That pancreatic edema and elevated serum enzyme levels may be the result of different cellular mechanisms in experimental pancreatitis is strongly suggested.

Amylases↗
PubMed1987

Xanthine oxidase activity in mouse pancreas: effects of caerulein-induced acute pancreatitis.

The development of acute pancreatitis involves a number of pathophysiological changes which result in pancreatic tissue damage. Data from several models of acute pancreatitis suggest that the in vivo conversion of the enzyme xanthine dehydrogenase to xanthine oxidase may cause tissue damage by the subsequent generation of oxygen-derived free radical products. In the present studies, acute pancreatitis was induced in mice by the administration of supramaximal secretory doses of caerulein, a cholecystokinin analogue. Pancreatic xanthine oxidase activity was observed to occur in the dehydrogenase form in both control and treated mice. Artifactual conversion to the oxidase form could be induced by exclusion of 2-mercaptoethanol and phenylmethylsulfonyl fluoride from the buffer during tissue preparation. These data indicate that no significant conversion of xanthine dehydrogenase to oxidase is associated with this model of acute pancreatitis in mice.

Acute Disease↗
PubMed1986

Severe colitis induced by soap enemas.

A patient had severe colitis after soap enemas for five days. Elimination of the soap enemas resulted in resolution of the colitis. We suggest that soap enemas be avoided.

Colitis↗
PubMed1985

Phosphatidylinositol hydrolysis and phosphatidylinositol 4',5-diphosphate hydrolysis are separable responses during secretagogue action in the rat pancreas.

Rat pancreatic fragments and acinar preparations were incubated in vitro to characterize further the changes in phosphoinositide metabolism that occur during secretagogue action. Two distinct responses were discernible. The first response, most notably involving a decrease in phosphatidylinositol content, was (a) observed at lower carbachol concentrations in dose-response studies, (b) inhibited by incubation in Ca2+-free media containing 1 mM EGTA, (c) associated with increases in inositol monophosphate production, and (d) provoked by all tissue secretagogues (carbachol, cholecystokinin, secretin, insulin, dibutyryl cAMP and the ionophore A23187), regardless of whether their mechanism of action primarily involved Ca2+ mobilization or cAMP generation. This decrease in phosphatidylinositol content was at least partly due to phospholipase C (and/or D) activation, as evidenced by the increase in inositol monophosphate. The second response, most notably involving markedly increased incorporation of 32PO4 into phosphatidic acid and phosphatidylinositol, was (a) observed at higher carbachol concentrations, (b) not influenced by incubation in Ca2+-free media containing 1 mM EGTA, and (c) associated with increases in inositol triphosphate production. This 32PO4 turnover response was probably largely the result of phospholipase C-mediated hydrolysis of phosphatidylinositol 4',5'-diphosphate, which, as shown previously, also occurs at higher carbachol concentrations and is insensitive to comparable EGTA-induced Ca2+ deficiency. This phosphatidylinositol 4',5'-diphosphate hydrolysis response was only observed in the action of agents (carbachol and cholecystokinin) which mobilize Ca2+ via activation of cell surface receptors. The present results indicate that phosphatidylinositol and phosphatidylinositol 4',5'-diphosphate hydrolysis are truly separable responses to secretagogues acting in the rat pancreas. Furthermore, phosphatidylinositol 4',5'-diphosphate, rather than phosphatidylinositol hydrolysis is more likely to be associated with receptor activation and Ca2+ mobilization.

Animals↗