Induction of drug-metabolizing enzymes in human pancreatic cancer and chronic pancreatitis.
Chronic pancreatitis and pancreatic cancer have both been linked with occupational exposure to organic chemicals. These chemicals are known to be metabolized within the liver by the cytochrome P-450 family of enzymes, and indeed are able to induce levels of these enzymes as evidence of their interaction. The purpose of this study was therefore to see if these enzyme systems were altered in chronic pancreatitis and pancreatic cancer. Immunocytochemistry of four phase I drug-metabolizing enzymes (cytochromes P-450 IIIA1, P-450 IIE, P-450 IA2, and NADPH cytochrome P-450 oxido-reductase) and one phase II enzyme [glutathione S-transferase (GST) 5-5] was therefore performed on pancreas and/or liver biopsy samples from organ donors and compared with patients with chronic pancreatitis or pancreatic cancer. In samples from donor subjects, the types and levels of drug-metabolizing enzymes in hepatocytes were similar to those seen in pancreatic acinar cells. In material from patients with chronic pancreatitis or pancreatic cancer, cytochrome P-450 enzyme levels were greater in both the liver and the pancreas than those seen in the donor group, while GST levels were unchanged. Islets of Langerhans showed high levels of P-450 IA2 in the donor group, with clear induction of P-450 IIIA1 and NADPH cytochrome P-450 oxidoreductase in patients with chronic pancreatitis but not in the pancreatic cancer group. Levels of GST 5-5 were also induced in the islets. The present findings raise the possibility of an aetiological relationship between elevated levels of drug-metabolizing enzymes and the subsequent development of disease.
ICI Central Toxicology Laboratory, Alderley Park, Cheshire, U.K.
J R
JR
Foster
J R
JR
Idle
J P
JP
Hardwick
R
R
Bars
P
P
Scott
J M
JM
Braganza
D001189:Aryl Hydrocarbon Hydroxylases; D015153:Blotting, Western; D002908:Chronic Disease; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D006801:Humans; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000096:biosynthesis; D010088:Oxidoreductases / Q000096:biosynthesis*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis; D010179:Pancreas / Q000201:enzymology*; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D010195:Pancreatitis / Q000201:enzymology*
D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C071207:1,2-dimethylhydrazine demethylase; D010089:Oxidoreductases, N-Demethylating; D009251:NADPH-Ferrihemoprotein Reductase