Loss of glutathione S-transferases in pollution-associated liver neoplasms in thite suckers (<i>Catostomus commerson</i>) from Lake Ontario

Stalker, Margaret; Kirby, Gordon M.; Kocal, T. E.; Smith, Ian R.; Hayes, Michael

doi:10.1093/carcin/12.12.2221

Cited by 19 publications

(11 citation statements)

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“…In contrast to rodents exposed to some mutagenic carcinogens (200), GST was deficient in FCA and hepatic neoplasms in white suckers exposed to PAH-contaminated sediments (182). The majority of DMBA and aflatoxin B 1-induced preneoplastic and neoplastic lesions in rainbow trout were also deficient for GST (104), although expression was induced in some FCA.…”

Section: Molecular Markersmentioning

confidence: 83%

Review Article: Experimental Chemical Carcinogenesis in Fish

Bunton

1996

Toxicol Pathol

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Dr. Bunton's primary research interest is on mechanisms of toxicity and carcinogenesis in fish related to environmental contamination and on the development of alternative models.Experimental carcinogenesis using fish species as alternative models is a dynamic field of research. The 1940's expansion of synthetic chemical producing industries coincided with a number of pollution-associated fish neoplasia epizootics, with polycyclic aromatic hydrocarbons as significant components of contaminated sediment in several cases. Epizootics of primarily liver and skin neoplasia in benthic species near coastal urban or industrial areas indicated the sensitivity of fish species to known mammalian carcinogens. Stressing a mechanistic approach, investigators have used data compiled from epizootics as the backbone of current research efforts to define carcinogenesis in fish species. With liver as the focus, patterns of neoplastic development similar to those seen in rodent bioassays have been induced in various fish species by genotoxic carcinogens. Similarities between fish and rodent models include chemical and species-specific responses to exposure and the development of predictable preneoplastic and neoplastic lesions. The expression of molecular molecules related to carcinogenesis is currently under investigation, which includes alterations in certain proteins, enzyme activity, and oncogene/tumor suppressor gene function. The potential for the application of research findings to both human and environmental health issues makes fish species attractive and valuable alternative models in carcinogenesis and toxicity research.Keywords. Medaka; methylazoxymethanol (MAM); molecular markers; N-methyl-N'-nitro-N-nitrosoguanidine (MNNG); Neoplasia; polycyclic aromatic hydrocarbons (PAH); rainbow trout INTRODUCTION Armed with data from fish neoplasia epizootics related to environmental synthetic chemical contamination, research has moved from the morphologic assessment of neoplasms to the identification of molecular mechanisms of neoplastic development and progression. The value of these studies can be argued along 2 lines that are often, but should not be, separated. One is for application to human health issues for which there is a chronic demand, and the other is the inherent value of monitoring the health of the environment, which includes all of the creatures therein. Unfortunately, it is the latter argument that most often has to be vigorously defended, although minimal reflection will reveal that we, too, are members of this population.The present review discusses experimental fish carcinogenesis by first presenting data from neoplasia epizootics that helped to form the framework of our current 604 research efforts. The effects of known direct and indirect carcinogens on various fish species from laboratory studies are then described to illustrate species similarities and differences in tissue response. The latter portion of the paper concentrates on chemical hepatocarcinogenesis and reviews the histologic and molecular marke...

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Section: Molecular Markersmentioning

confidence: 83%

Review Article: Experimental Chemical Carcinogenesis in Fish

Bunton

1996

Toxicol Pathol

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“…Reduced expression of these subunits has been attributed either to dedifferentiation (58) or to differential subunit expression during more rapid cell proliferation (59,60). Also, advanced hepatocellular neoplasms in fish exposed environmentally (19) or experimentally (18) to genotoxic carcinogens are GST deficient. Thus, preexisting or acquired defects in GSTdependent resistance are becoming recognized as an important feature in various neoplastic conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies on the pathogenesis of liver neoplasia have shown that progression of pollution-associated liver neoplasms in fish is associated with a loss of hepatic GST expression, both in white suckers from Lake Ontario and in experimentally induced liver neoplasms in rainbow trout (18,19). We have proposed that this loss of GST-associated resistance might increase the susceptibility of preneoplastic populations of hepatocytes to some unidentified exogenous or endogenous genotoxic substances that are putatively responsible for further DNA damage during malignant progression.…”

Section: -158)mentioning

confidence: 99%

Reduced Expression of Glutathione S–Transferase Yb2 During Progression of Chemically Induced Hepatocellular Carcinomas in Fischer 344 Rats

et al. 1994

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We followed the expression of several glutathione S-transferase subunits in altered foci, liver neoplasms and metastases produced in male Fischer 344 rats by a modified Solt-Farber protocol, to determine whether components of the resistant phenotype are lost during neoplastic progression. At 6 mo after initiation, altered foci and persistent nodules displayed increased immunohistochemical expression of glutathione S-transferase subunits Yf (r-class), Ya (a-class) and Ybl (p-class) in comparison with normal or surrounding liver tissue. However, although most altered foci exhibited little change in glutathione S-transferase Yb2 (p-class) subunit expression, 5% of Yf-positive foci and nodules were partially or completely deficient in Yb2 expression. At 12 and 18 mo after initiation, most grossly visible hepatocellular tumors retained induced expression of glutathione S-transferase subunits Yf, Ya and Ybl, but 63% of the carcinomas, 88% of the primary metastatic carcinomas and 94% of the pulmonary metastases were deficient in Yb2 expression. These differences in glutathione S-transferase subunit expression were confirmed by quantitative analysis by reverse-phase HPLC of S-hexylglutathione affinitypurified glutathione S-transferases from advanced tumors. Cytosolic glutathione S-transferase activity for truns-4-phenyl-3-buten-2-one in advanced tumors ranged from 42% to 66% of the activity in matched surrounding liver, whereas glutathione S-transferase activities for l-chloro-2,4-dinitrobenzene were increased by 140% to 161%. These studies demonstrate that progression of hepatocellular carcinomas in the resistant hepatocyte model of carcinogenesis in which several glutathione S-transferase subunits are induced is associated with the loss of a major constitutive p-class hepatic glutathione S-transferase. Although the mechanism and role of the reduction or loss of glutathione S-transferase Yb2 during malignant progression are unknown, we propose that loss of glu-

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“…These observations suggest that the resistant phenotype of preneoplastic hepatocytes might favor their selective expansion during exposure to the toxic effects of bile acids. GSTs bind and transport bile acids intracellularly, and this binding inhibits GST activity in vitro (5,17,30,39,46,47 (25,41). Also, white suckers from sites where pollution-associated liver neoplasms occur have an inflammatory cholangiohepatitis that substantially reduces hepatic GST activity (24).…”

Section: Introductionmentioning

confidence: 99%

“…Also, white suckers from sites where pollution-associated liver neoplasms occur have an inflammatory cholangiohepatitis that substantially reduces hepatic GST activity (24). Accordingly, we have proposed that loss or inhibition of GST activity might favor malignant progression by increasing susceptibility of hepatocytes to genotoxic damage by exogenous or endogenous compounds normally detoxified by these enzymes (25,41 Enzyme activities for 1-chloro-2,4-dinitrobenzene (CDNB) and trans-4-phenyl-3-buten-2-one (tPBO) were determined at 25°C (15 (Fig. 3).…”

Section: Introductionmentioning

confidence: 99%

Influences of Dietary Deoxycholic Acid on Progression of Hepatocellular Neoplasms and Expression of Glutathione S-Transferases in Rats

et al. 1994

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Serial magnetic resonance imaging (MRI) was used to evaluate the influences of dietary deoxycholic acid (DCA) on the rate of progression of chemically induced hepatocellular neoplasms in rats. Male Fischer-344 rats with established persistent hepatocellular nodules generated by the Solt-Farber protocol were exposed to dietary DCA (0.3%) between 6 and 12 mo of age. Growth of nodules and carcinomas in vivo was measured by morphometric quantification of tumor images obtained every 6 wk. The final stages of neoplastic progression were determined by terminal histopathological examination and by expression and functional evaluation of glutathione S-transferase (GST) isoenzyme phenotypes. Dietary DCA increased the number of hepatocellular neoplasms per rat, accelerated the rate of growth of persistent nodules, and increased the histological progression of liver tumors. Expression of immunoreactive GST subunits Yf, Ya, and Yb 1 was induced in early persistent nodules, a pattern that was maintained throughout the study in both basal diet and DCA-fed groups. However, 5% of early nodules and about 75% of advanced neoplasms were partially or completely deficient in GST Yb2 expression in both groups. DCA did not alter the cytosolic activity for the GST substrates 1-chloro-2,4-dinitrobenzene (CDNB) or trans -4-phenyl-3-buten-2-one (tPBO) in tumors or surrounding liver. However, in both groups, CDNB activity was increased in the tumors relative to the surrounding nonneoplastic tissue, whereas activity for tPBO, a substrate more specific for the Yb2 subunit, was reduced in the tumors. All advanced neoplasms were similarly more resistant than surrounding liver to DNA-binding metabolites of aflatoxin B 1 or benzo [a]pyrene. These data demonstrate that DCA can increase the progression of established hepatocellular nodules to larger, more advanced neoplasms but does not preferentially select for a specific GST phenotype. Preferential loss of constitutively expressed GST Yb2 in both basal diet and DCA-fed groups may be an important aspect of progression from resistant nodules to advanced cancers in this model. These studies also demonstrate that serial MRI is a useful tool for measuring the rates of enlargement and patterns of growth in established hepatocellular neoplasms.

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Loss of glutathione S-transferases in pollution-associated liver neoplasms in thite suckers (Catostomus commerson) from Lake Ontario

Cited by 19 publications

References 0 publications

Review Article: Experimental Chemical Carcinogenesis in Fish

Review Article: Experimental Chemical Carcinogenesis in Fish

Reduced Expression of Glutathione S–Transferase Yb2 During Progression of Chemically Induced Hepatocellular Carcinomas in Fischer 344 Rats

Influences of Dietary Deoxycholic Acid on Progression of Hepatocellular Neoplasms and Expression of Glutathione S-Transferases in Rats

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