INDUCIBILITY OF CYTOCHROMES P-4502E1 AND P-4501A1 IN THE RAT PANCREAS

Cytochrome P-450 (CYP) isoenzymes have been incriminated in the toxici ty and carcinogenicity of various xenobiotics in different tissues, bu t prior measurements of their activity in pancreatic microsomes have b een disappointing. We now applied new isolation methods and a highly s ensitive procedure to assay for the metabolism of p-nitrophenol and 7- ethoxyresorufin, specific substrates for CYP2E1 (2E1) and CYP1A1 (1Al) , respectively. 2E1 and 1Al content was estimated with high-resolution chemiluminescent Western blots using recombinant 261 and 1A1 as stand ards. We found that p-nitrophenol hydroxylase activity was 5.07 +/- 0. 66 and 1.50 +/- 0.26 pmol/ min/mg of protein in pancreatic microsomes of ethanol-fed and control rats, respectively. Chronic ethanol treatme nt increased 2E1 content in pancreatic microsomes 3.6-fold. Activity a nd content of 2E1 were also assessed in hepatic microsomes: specific a ctivity (expressed per 2E1 content) was similar in pancreatic and hepa tic microsomes, There was also an inductive effect of 3-methylcholanth rene (MC) on 1A1 in pancreatic microsomes. Pancreatic microsomal 7-eth oxyresorufin-O-dealkylation activity in MC-treated rats was 19.6 +/- 1 .7 pmol/min/mg of protein, 61-fold higher than in controls, MC treatme nt increased the 1A1 content in pancreatic microsomes 42-fold. These r esults demonstrate that, in pancreatic microsomes, ethanol and MC exer t striking inductive effects on 2E1 and 1A1 activities, which could pl ay a role in the pathogenesis of pancreatitis and/or pancreatic cancer .