Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149521 (chronic pancreatitis)
 7,199 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present work reviews the evidence for an involvement of free radicals in the pathophysiology of chronic pancreatitis and the potential of treatment with antioxidant and scavenger substances. Preliminary results indicate that exposure of isolated pancreatic acinar cells to a reaction mixture containing hypoxanthine, xanthine oxidase, and chelated iron causes cell damage and death probably due to generation of superoxide anion and hydrogen peroxide. It still needs to be analyzed which scavengers and antioxidants are able to ameliorate the damage due to oxidant stress in cell models. Such knowledge from cellular studies might help to plan therapeutical trials to evaluate potentially effective antioxidants and scavengers in the experimental animal and in patients with pancreatitis. As yet there are no published studies about the role of free radicals in animal models of chronic pancreatitis. This fact is probably due to the shortcomings of the animal models available. Recent studies presented evidence that activation of oxygen-derived free radicals occurs in patients with chronic pancreatitis. There is also some evidence that the dietary intake of antioxidants may be reduced in patients with chronic pancreatitis. It was suggested that such reduction of antioxidant defenses in the face of an increased demand due to heightened induction of P450 activities may facilitate lipid peroxidation. However, as yet, there is no direct evidence that a reduction of dietary antioxidants with a simultaneous increase in P450 activity is the primary mechanism which initiates chronic pancreatitis without contribution of other factors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Involvement of free radicals in the pathophysiology of chronic pancreatitis: potential of treatment with antioxidant and scavenger substances. 179 74

Functional and morphological changes in hepatocytes, indicating induction of the drug metabolizing enzymes and free radical-mediated damage, were found in 4 patients with idiopathic chronic pancreatitis. The possibility that reflux of abnormal bile (rich in lipid peroxidation and other products generated through hepatic metabolism of xenobiotics) into the pancreatic duct may initiate pancreatic damage was negated when bile duct ligation and bile diversion did not abolish attacks of pancreatitis in 3 cases, although the evidence of reflux was indisputable in 1 of them who also had a pancreatoduodenectomy. Pancreatic acinar cells from that patient showed extensive microvesiculation, as did hepatocytes from each case. These observations suggest that pancreatic and liver damage in chronic pancreatitis proceed independently but by the same mechanism-heightened, but unmitigated, oxidative detoxification of xenobiotics by cytochromes P450. Therefore, although bile reflux is not a prerequisite, it could compound injury in the head of the gland. Antioxidants were prescribed to the 3 cases mentioned and, from the outset, to a fourth patient who showed the same liver changes. This unconventional approach has held attacks at bay during a follow-up period of 5 yr.
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PMID:Abnormal drug metabolism in chronic pancreatitis. Treatment with antioxidants. 222 7

Three markers of free radical oxidation of lipids--9 cis, 11 trans isomer of linoleic acid, conjugated dienes and ultraviolet fluorescence products--were measured in the phospholipid fraction of duodenal juice collected in the first 10 min after an intravenous injection of secretin. The volume of aspirate was similar in 11 controls and in 25 patients who had sustained an attack of pancreatitis 6 weeks earlier--acute pancreatitis (AP) 10, chronic pancreatitis (CP) 15. The concentration of each marker was very significantly higher in the patients; the output of the isomer gave the best discrimination from controls; and ultraviolet fluorescence products were substantially higher in the subgroup with CP than with AP. The serum % molar ratio of the isomer to linoleic acid was measured in 25 controls, 14 AP and 17 CP patients: the highest levels were found in the CP group. Heightened hepatic free radical activity involving lipid isomerization as well as lipid peroxidation pathways is a feature of pancreatitis--probably antedating the attack and persisting well after clinical recovery--the difference between CP and AP being in the degree of abnormality. We argue that these hepatic changes mirror changes in pancreatic-acinar cells and that increased free radical activity in both organs is due to a shortfall of antioxidants in the face of cytochromes P450 induction by xenobiotics. Therefore, a combination of preventive and chain-breaking antioxidants may be useful in preventing further attacks of pancreatitis and controlling background pain in chronic disease.
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PMID:Heightened free radical activity in pancreatitis. 237 63

Our published dietary and pharmakokinetic studies in 15 patients with idiopathic chronic pancreatitis and 15 age- and sex-matched controls suggested that a combination of subnormal antioxidant intakes and chronic induction of the cytochromes P450 facilitates the pancreatic problem. We have now attempted to determine the relative importance of these two factors by studying a group of 15 institutionalized patients with epilepsy (EP), but without abdominal pain, who were on long-term treatment with anticonvulsant inducers of cytochromes P450 so that their clearance of theophylline (which reflects cytochromes P450 activities, and thereby provides an index of antioxidant demand) was as high as in the patients with chronic pancreatitis (CP) (mean +/- s.d., 123 +/- 59 ml/kg/h versus 120 +/- 62 respectively), and significantly higher than in controls (74 +/- 16 ml/kg/h, P less than 0.02). Canonical variate analysis of the drug kinetic and dietary data provided two functions with which to separate the three groups. The first function, heavily weighted on selenium, separated the controls from the other two groups whose values were lower; the second function, equally weighted on methionine and vitamin C, separated the EP group from the CP group whose values were generally lower. The results suggest that enzyme induction per se is not the critical factor in the development of CP. Instead, suboptimal availability of antioxidants in the face of increased demand--in particular of those substances that protect cells against non-biological free radicals--may be the key consideration, a deduction reinforced by observations in patients with epilepsy who went on to develop chronic pancreatitis.
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PMID:Antioxidants, enzyme induction, and chronic pancreatitis: a reappraisal following studies in patients on anticonvulsants. 322 2

The rising trend of idiopathic pancreatitis, and our demonstration that cytochromes P450 are 'induced' in most patients, prompted a search for enzyme inducers in their work environments. The findings in 19 patients (chronic pancreatitis 15, acute pancreatitis 4) are described. In the initial series of 12 consecutive patients with idiopathic pancreatitis, the enquiry revealed regular exposure to diesel exhaust fumes in 6 patients (of whom one had also been exposed to ozone and metal oxides), perchloroethylene or trichloroethylene in 3, paint solvents in a further 3. A second series included the next 7 patients with pancreatitis who drank alcohol on a daily basis for several years before their first symptom, but whose attacks continued although they had become, and remained, teetotal: their current occupations involved regular exposure to diesel exhaust fumes in 5 patients, to paint solvents in 1, and to trichloroethylene in 1. The wide variation in the duration of exposure before the first symptom, 2-21 yr, may reflect the net effect on cytochromes P450 of other xenobiotics (e.g. alcohol, cigarettes, caffeine). In several patients, symptoms stopped on removal from exposure to volatile chemicals but recurred on re-exposure. These preliminary findings suggest that occupational exposure to aromatic or chlorinated hydrocarbons may be relevant not only in idiopathic pancreatitis but also in alcohol-related pancreatic disease.
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PMID:Occupational chemicals and pancreatitis: a link? 332 Feb 24

The case history of a 10-yr old boy with calcific chronic pancreatitis is reported. His theophylline clearance of 450 ml/kg/h was several times higher than normal, indicating induction of cytochromes P450. Painful attacks disappeared concurrently with administration of antioxidants. The possible relevance of these findings is discussed in the context of chronic pancreatitis in childhood.
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PMID:Antioxidants to treat chronic pancreatitis in childhood? Case report and possible implications for pathogenesis. 336 Nov 61

Fifteen patients with idiopathic chronic pancreatitis (aged 17-78 years), who had not altered their diet since their first symptoms, completed 7-d weighed dietary records at home. The computed information was compared with that from 15 age- and sex-matched volunteers. Attention was focussed on the intakes of antioxidants and unsaturated fatty acids. The patients ingested less selenium, vitamin E, vitamin C and riboflavin than did controls (P less than 0.001, P less than 0.02, P less than 0.001 and P less than 0.05 respectively, using paired t-tests): selenium was by far the best discriminator on step-wise analysis. When the selenium intakes were examined alongside the results of theophylline tests--which reflect cytochromes P450 activities and, thereby, provide an index of antioxidant demand--a line of discrimination separated the majority of patients (with faster drug clearances and lower selenium intakes) and controls. There were no differences in the intakes of individual unsaturated fatty acids, C14:1 through to C24:6, between the two groups. However, amongst six subjects in the overlap zone, three with chronic pancreatitis habitually ate greater amounts of highly unsaturated fatty acids C20:4 to C24:6 inclusive (1970, 1049, 750 mg/d) than did three controls (329, 320, 82 mg/d). Animal experiments show that suboptimal intakes of dietary antioxidants and/or excessive intakes of highly unsaturated fatty acids and/or induction of cytochromes P450 facilitate peroxidation of cellular lipid membranes by free radicals. Our dietary data, taken in conjunction with pharmacokinetic data, thus suggest that a similar situation--favouring lipid peroxidation--may underlie human chronic pancreatitis.
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PMID:Dietary antioxidants and chronic pancreatitis. 395 20

Micronutrient antioxidants interact with glutathione in tissues to facilitate the disposal of reactive oxygen species and xenobiotic metabolites derived via cytochromes P450. Published evidence linking cytochrome P450I induction with chronic pancreatitis therefore led us to compare antioxidant status in patients at Manchester in the northwest of England and at Madras in the southeast of India. Serum studies in healthy volunteers showed that the biologic availabilities of selenium and alpha-tocopherol were equally high in the two zones but that the availabilities of beta-carotene and ascorbic acid were lower in the tropical area (p < 0.001), where the ratio of ascorbic acid to total vitamin C concentration in serum was substantially reduced (p < 0.001). The serum antioxidant profiles of the chronic pancreatitis groups reflected these indigenous differences: a decrement in selenium and alpha-tocopherol was evident in both zones, whereas beta-carotene and ascorbic acid values were subnormal only in the Manchester group. The concentration of inorganic sulphate in urine--an index of long-term intake of sulphur amino acids for synthesis of glutathione and other detoxifiers--was similar in controls and patients from Manchester, but levels were lower than in their Madras counterparts (p < 0.02, p < 0.01, respectively). The results suggest that culinary practices that erode the biologic availabilities of ascorbic acid and beta-carotene may predispose to pancreatic oxidative stress and thereby to the changes leading to chronic pancreatitis at an early age in south India. These findings have implications for treatment and prophylaxis.
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PMID:Micronutrient antioxidant status in tropical compared with temperate-zone chronic pancreatitis. 830 14

Dr. Joan Braganza, a world expert in the field of chronic pancreatitis, proposed a new template for its pathogenesis based on the role of free radical pathology, in particular the heightened but unmitigated oxidative detoxification reactions via cytochromes P450. Dr. Braganza has gone on to show how pancreatic damage in cystic fibrosis, acute pancreatitis and pancreatic cancer fit into the scheme, paving the way for new treatment modalities. In this interview, Dr. Braganza shares her life experience as an investigator and provides a perspective for young researchers entering the field of pancreatology.
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PMID:'Not knowing something is normally a milestone on the way to knowledge'. An interview with Joan M. Braganza, DSc, FRCP, FRCPath, Reader Emeritus, University of Manchester, UK. 1988 83