Up-regulation of cytochrome P450 1A2, 2C9, and 2E1 in chronic pancreatitis.
The oxidative metabolism of xenobiotics is effected mainly by cytochrome P450 enzymes (CYP), which are expressed as a family of genetically related enzymes primarily in hepatocytes. The pancreas is among the extrahepatic tissues expressing CYP, and it has been suggested that intermediates generated by them might be of pathogenetic significance for diseases of the pancreas such as chronic pancreatitis. We studied 10 surgical resection specimens by immunohistochemistry with polyclonal antibodies against recombinant human CYP 1A1, 1A2, 2C9, 2E1, and 3A and used tissues from 11 normal pancreata as controls. In addition, we assayed microsomal preparations for their capacity to metabolize verapamil. In normal pancreata weak to moderate expression of all enzymes was demonstrated immunohistochemically in up to 50% of duct epithelia, acinar cells, and islet cells. In contrast, in chronic pancreatitis an up-regulation was observed, with immunohistochemical positivity in some cases in up to 100% of duct epithelia and acinar cells. The oxidative capacity of microsomal preparations from chronic pancreatitis was higher than that of preparations obtained from control tissues; compared to liver microsomes, however, it was low. The up-regulation of CYP may have pathogenetic significance for chronic pancreatitis. Yet considering the pancreas' capacity for conjugation reactions, conceivably low levels of reactive intermediates could effectively undergo inactivation.
Wacke
R
R
Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, University of Rostock, Germany.
Kirchner
A
A
Prall
F
F
Nizze
H
H
Schmidt
W
W
Fischer
U
U
Nitschke
F P
FP
Adam
U
U
Fritz
P
P
Belloc
C
C
Drewelow
B
B
D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases; D002908:Chronic Disease; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008875:Middle Aged; D010084:Oxidation-Reduction; D010179:Pancreas / Q000378:metabolism; D010195:Pancreatitis / Q000201:enzymology*; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000096:biosynthesis*; D015854:Up-Regulation; D014700:Verapamil / Q000378:metabolism
D003577:Cytochrome P-450 Enzyme System; D014700:Verapamil; D013250:Steroid Hydroxylases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D039181:Steroid 16-alpha-Hydroxylase