Xenobiotic Metabolism, Oxidant Stress and Chronic Pancreatitis

Abstract

Chronic pancreatitis, although relatively rare in the Western World, is common in certain tropical zones where staple crops such as cassava are rich in cyanogenic glycosides. This paper reviews the evidence for a cyanide connection, with reference to experimental studies using another plant nitrile, crambene; and then examines the hypothesis that chronic pancreatitis represents a manifestation of uncoordinated detoxification reactions between pancreatic cytochrome P450 mono-oxygenases and phase II conjugating enzymes, resulting in the irreversible consumption of glutathione in the acinar cell. The conclusion is that the central role of disrupted pancreatic glutathione status, as a result of ‘xenobiotic stress’, in the evolution of chronic pancreatitis cannot be overestimated. This position contrasts with that in acute pancreatitis, in which glutathione depletion has a pivotal role too, but occurs as a result of ‘stress’ from reactive oxygen species.

Functional polymorphisms of UDP-glucuronosyltransferases 1A1, 1A6 and 1A8 are not involved in chronic pancreatitis

“…important mechanisms involved in host defence against xenobiotic chemicals and endogenous toxins. Xenobiotically or endogenously mediated cellular injury might play a role in the etiology of CP [37][38][39]. In the present study we investigated the possible association between CP and genetic polymorphisms in three UGT1A isoenzymes that are associated with changes in enzyme activity and function and are potentially expressed in pancreatic tissue [20,[25][26][27]30,31].…”

Micronutrient ('Antioxidant') Therapy for Chronic Pancreatitis: Basis and Clinical Experience

“…The best explanation is that xenobiotics hit the gland directly via the arterial route, whereas ingested toxicants first encounter the liver which is best equipped to deal with RXS, via its huge complement of GSH and GST (21,170). This is illustrated by experimental studies in the 1950s using a subcutaneous dose of carbon tetrachloride, which is processed by CYP to yield RXS : damage in advance of liver injury; lesions that could be "produced at will" by varying the dose, ranging from patchy lesions of early chronic pancreatitis with or without concretions, through to 'pancreatic cirrhosis' or a cystic fibrosis-like picture (165).…”

“…This is illustrated by experimental studies in the 1950s using a subcutaneous dose of carbon tetrachloride, which is processed by CYP to yield RXS : damage in advance of liver injury; lesions that could be "produced at will" by varying the dose, ranging from patchy lesions of early chronic pancreatitis with or without concretions, through to 'pancreatic cirrhosis' or a cystic fibrosis-like picture (165). The theme is reinforced by more recent studies with nitriles akin to those in dietary cassava (manioc, tapioca), and the occupational chemical dibutyltin (170), showing that prior induction of CYP2E1 by a small dose of ethanol augments dibutyltin injury (101) -as is also true for hepatotoxicity from volatile hydrocarbons (131,149). As to chronic exposure to ethanol, laboratory studies show that increased FRA precedes pancreatic injury (71).…”

“…and GSH, glutathionine. Other abbreviations: MTA methylthioadenosine; ATP adenosyl triosephosphate; Pi, activated phosphate groups; iSO 4, inorganic sulphate; B 2 , B 6 , B 12, riboflavin, pyridoxine and cobalamin, respectively; GSH.Px, glutathione peroxidase; GSH.Rx, glutathione reductase; Se, selenium; GSSG, oxidised glutathione on engaging with peroxides; GSSR, conjugates of glutathione with electrophiles from xenobiotics; NADPH and NADP, reduced and oxidized forms of nictotinamide adenosine phosphatase, respectively; DP, 5-OP and GCT, enzymes involved in the synthesis of glutathione (170). Asterisks indicate enzymes that are known to be vulnerable to electrophilic / oxidative stress.…”

“…The same is true for GSH: besides facilitating exocytosis and inhibiting proteases, it helps in redox control, serves as a reservoir for cysteine, mops up hydrogen and lipid peroxides, detoxifies RXS and contributes to the extracellular antioxidant shield. Whereas its utilisation in peroxide control is soon made good via interlocking GSH peroxidase-GSH reductase, NADPH-NADP, and glucose 6 phosphate-ribose 5 phosphate shuttles, it is permanently excreted from cells in conjugates with RXS ( Figure 2) (21,170). In these circumstances, the ability of ascorbic acid to substitute for GSH by redox and non-redox pathways is invaluable (30), as is heightened activity of gamma glutamyl transpeptidase (γGT) in the plasma membrane, which enables the uptake of reconstituting amino acids from the plasma GSH pool (138,170) but these resources are finite.…”