Phase Ii Metabolizing Enzymes Glutathione Stransferases

The fate of the active intermediates of the Phase I reaction is governed by the Phase II detoxifying enzymes, like GSTs, in conjugation with glutathione or reduction reactions, resulting in less toxic and readily excreteable metabolites.32,34,36 It is assumed that GSTs are one of the major detoxification systems that protect cells from cytotoxic and carcinogenic insults.34,47 Therefore, the extent and duration of bioactivated toxic or carcinogenic compounds in an organ depend on the interplay of both biotransforming enzyme systems. Clearly, the yield of these metabolites would be higher if cells were rich in Phase I bioactivating enzymes, but poor on detoxifying Phase II enzymes.

As with Phase I metabolizing enzymes, genetic variation in Phase II enzymes metabolizing pancreatic carcinogens, such as heterocyclic and aromatic amines, could determine the risk of developing pancreatic diseases. Again, as with Phase I metabolizing enzymes, the reported data on polymorphisms and cancer susceptibility are contradictory. In a case control study by Bartsch et al., whole blood cell samples collected from Caucasian patients with pancreatic cancer, nonalcoholic and alcoholic pancreatitis, and from asymptomatic control subjects were analyzed for the effect of genetic polymorphism of different Phase II metabolizing enzymes on the risk of pancreatic diseases (cancer, pancreatitis).63 A significant overrepre-sentation of the GSTM1 AB or GSTM1 B genotype was found in all pancreatic disease cases combined. Only a modest increase in susceptibility to pancreatic diseases could be found to be associated with the polymorphism of GSTM1 enzymes. On the contrary, a prospective study of 149

unselected incident cases of pancreatic adenocarcinoma and 146 ethnically matched controls by Liu et al. found no associations between GSTM1 polymorphism and pancreatic cancer susceptibility.54 In a population-based case-control study, conducted in six San Francisco Bay area counties from 1994 to 2001, an association between homozygous deletions of two GST genes, GSTM1 and GSTT1; smoking; and pancreatic cancer was analyzed.53 In this population, homozygous deletions of the GSTM1 and GSTT1 genes alone did not affect the risk of pancreatic cancer. An interaction between the GSTT1-null genotype and cigarette smoking was observed, especially among women. Therefore, in this subpopulation, the combination of a deletion polymorphism in GSTT1 and heavy smoking might be associated with an increased susceptibility of pancreatic cancer. It should be noted that subjects for this study were exclusively of the Caucasian population and that ethnic and genetic factors are known to substantially influence the expression pattern of drug-metabolizing enzymes.10,63,64

In 1994, Collier and coworkers systematically investigated the immu-nohistochemical expression of GST-a, GST-^, and GST-n in specimens from the normal pancreas and from patients with pancreatic cancer.65 Anti-GST-^ was not immunoreactive either in normal or cancer specimens. Malignant cells expressed GST-n alone in more than half of the cancer specimens. In only 8% of the malignancies, GST-n and GST-a were expressed in parallel; in another 8%, GST-a was exclusively expressed. In healthy control specimens, the anti-GST-n antibody was immunoreactive in intralobular ducts and centroacinar cells, and large ducts expressed GST-n and GST-a in parallel. Acinar cells expressed only GST-a. From these results, Collier et al. came to the conclusion that the GST expression could possibly reflect the cells of origin, suggesting that the tumor arises from the centroacinar cells or intralobular ducts, a possibility that was already discussed in the early 1980s.66-68

In one of the most recent studies, Verlaan et al. investigated whether polymorphisms in the GSTM1, GSTT1, and GSTP1 genes modify the risk for chronic pancreatitis.69 In this study, the rates of GSTT1 and GSTP1 genotypes did not differ between chronic pancreatitis patients and healthy controls. GSTM1 null genotypes, on the other hand, were significantly less common in patients with chronic pancreatitis induced by alcohol as compared to alcoholics without pancreatitis and normal controls. The authors concluded that GSTM1 null alcohol users are less susceptible to chronic pancreatitis.

Furthermore, the cellular localization of the most frequently expressed GSTs — a, and n — was studied in the normal pancreas and in tissue samples from primary chronic pancreatitis, secondary chronic pancreatitis resulting from ductal obstruction by cancer, and pancreatic cancer patients.47,70 Ductal and ductular cells of all three groups as well as cancer cells expressed GST-n. Acinar cells were not stained in any specimen. A various number of islet cells was strongly immunoreactive. Significantly more islet cells expressed GST-n in chronic pancreatitis specimens than in the normal controls or pancreatic cancer specimen. Interestingly, the GST-n expression in islet cells was restricted to glucagon cells, however, not all glucagon cells expressed the enzyme. To examine whether the overexpression or deficiencies of GST-n are compensated for by other GST isozymes, the expression of GST-a and GST-^ was investigated in the same specimens.70 Compared to the normal pancreas, the expression of all three GSTs was higher in the ductal, acinar, and islet cells of primary chronic pancreatitis, but conversely, it was lower in the secondary chronic pancreatitis. Unlike the GST-n, the distribution of GST-a and GST-^ within islets did not show marked differences between the three groups. The reactivity of cancer cells to GST-a and GST-n antibodies was similar to that of ductal cells in the normal pancreas, chronic pancreatitis, and secondary chronic pancreatitis, but 55% of cancers did not express GST-suggesting an association between pancreatic cancer and the lack of GST-^ expression. The lack of GST-^ expression is in line with findings in other cancers.71 Contrary to previous studies,65,72,112 an expression of GST-a was found in islet cells. The reason for the differing results could be the small number of islet cells expressing GST-a (up to 10%).

Contrary to the findings on Phase I metabolizing enzymes, which were more frequently expressed in islet cells of the head, GST-^ and GST-n were expressed primarily in islets of the body and tail. GST- a was expressed in islet cells of one-half of the specimens, regardless of their anatomic origin.28 As with GST-n, the expression of GST-a within all islets was restricted to a-cells; the GST-^ antibody had no preference for a special endocrine cell type.47,70

The fourth class of enzymes, GST-0, was also investigated by Foster et al.30 Contrary to the findings on CYPs, GST levels of the liver and the pancreas were similar between healthy individuals and pancreatic cancer patients. In specimens from patients with chronic pancreatitis, elevated GST-0 levels were found in the islets of Langerhans.

Recently Trachte et al. investigated abnormalities in gene expression in ductal adenocarcinoma of the pancreas in comparison with the normal pancreas by using cDNA arrays and immunohistochemistry.74 While evaluating approximately 2000 genes, they found, contrary to the results of Ulrich et al., an upregulation of GST-n in all investigated adenocarcinomas.

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Diabetes 2

Diabetes 2

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