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J K Reddy

Publications and source records attributed to J K Reddy.

At least 163 records · Page 9Linked to original sources
PubMed1985

Induction of fatty acid beta-oxidation and peroxisome proliferation in the liver of rhesus monkeys by DL-040, a new hypolipidemic agent.

Many structurally unrelated hypolipidemic agents and certain phthalate-ester plasticizers induce hepatomegaly and proliferation of peroxisomes in liver parenchymal cells of rodents, but there is relatively limited evidence regarding the ability of such compounds to induce peroxisome proliferation in the livers of nonrodent species including man. The present study was designed to determine if DL-040 (4-(((1,3-benzodioxol)-5-yl)methyl)amino-benzoic acid), a newly developed hypolipidemic agent, induces peroxisome proliferation in the liver of adult rhesus monkeys. Feeding of DL-040 (300 mg/kg body wt for 1 week; and 400 mg/kg body wt for 10 weeks) caused a significant increase in peroxisome population as determined by ultrastructural and morphometric analyses. The DL-040-induced peroxisome proliferation was accompanied by increases in the levels of catalase, carnitine acetyltransferase and the peroxisomal fatty acid beta-oxidation system. As expected, DL-040 caused a significant reduction of serum cholesterol and low density lipoprotein content. These data suggest that hepatic peroxisome proliferation is inducible in nonhuman primates at dose levels that exceed therapeutic levels.

Aminobenzoates↗
PubMed1985

Specific changes in the protein composition of rat liver in response to the peroxisome proliferators ciprofibrate, Wy-14,643 and di-(2-ethylhexyl)phthalate.

The hypolipidaemic agents ciprofibrate and Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid) and the phthalate-ester plasticizer di-(2-ethylhexyl)-phthalate (DEHP), like other peroxisome proliferators, produce a significant hepatomegaly and induce the peroxisomal fatty acid beta-oxidation enzyme system together with profound proliferation of peroxisomes in hepatic parenchymal cells. Changes in the profile of liver proteins in rats following induction of peroxisome proliferation by ciprofibrate, Wy-14,643 and DEHP have been analysed by high-resolution two-dimensional gel electrophoresis. The proteins of whole liver homogenates from normal and peroxisome-proliferator-treated rats were separated by two-dimensional gel electrophoresis using isoelectric focusing for acidic proteins and nonequilibrium pH gradient electrophoresis for basic proteins. In the whole liver homogenates, the quantities of six proteins in acidic gels and six proteins in the basic gels increased following induction of peroxisome proliferation. Peroxisome proliferator administration caused a repression of three acidic proteins in the liver homogenates. By the immunoblot method using polyspecific antiserum against soluble peroxisomal proteins and monospecific antiserum against peroxisome proliferation associated Mr 80000 polypeptide (polypeptide PPA-80), the majority of basic proteins induced by these peroxisome proliferators appeared to be peroxisomal proteins. Polypeptide PPA-80 becomes the most abundant protein in the total liver homogenates of peroxisome-proliferator-treated rats. These results indicate that ciprofibrate, DEHP and Wy-14,643 induce marked changes in the profile of specific hepatic proteins and that some of these changes should serve as a baseline to identify a set of gene products that may assist in defining the specific 'peroxisome proliferator domain'.

Animals↗
PubMed1985

Lack of covalent binding of peroxisome proliferators nafenopin and Wy-14 643 to DNA in vivo and in vitro.

[3H][2-methyl-2-p-(1,2,3,4-tetrahydro-naphthyl)phenoxy] propionic acid (nafenopin), a hepatocarcinogenic peroxisome proliferator, when administered p.o. to normal intact and partially hepatectomized male F344 rats did not show any significant binding to DNA and RNA, but bound to proteins. The in vitro incubation of [3H]nafenopin and [3H]4-chloro-[6-(2,3-xylidino)pyrimidinylthio]acetic acid (Wy-14643), another peroxisome proliferator, with hepatic microsomes and calf thymus DNA also showed no significant binding of these chemicals to DNA.

Animals↗
PubMed1985

32P-postlabeling analysis of peroxisome proliferator-DNA adduct formation in rat liver in vivo and hepatocytes in vitro.

Hepatocarcinogenic peroxisome proliferators, clofibrate, ciprofibrate, Wy-14643 or di(2-ethylhexyl)phthalate, were administered once daily by gavage to groups of three male F344 rats for 3 days and the rats were killed 2 h after the last dose. The DNA isolated from the livers was analyzed for possible carcinogen-DNA adducts, by a most sensitive 32P-postlabeling technique which can detect one adduct in 10(10) nucleotides. No adducts were detected by this assay in the DNA isolated from the livers of rats treated with any of the peroxisome proliferators. Adducts were also not found in the DNA of hepatocytes exposed in vitro to these peroxisome proliferators for 4 h in primary suspension cultures. Failure to detect peroxisome proliferator DNA adducts in hepatocytes under in vivo and in vitro conditions supports the contention that formation of a peroxisome proliferator-DNA adduct is not an essential step in the carcinogenesis by this novel class of carcinogens.

Animals↗
PubMed1985

Demonstration of kallikrein in a rat pancreatic acinar cell carcinoma.

Kallikrein was identified immunohistochemically and biochemically in a transplantable pancreatic acinar cell carcinoma of the rat. The concentration of immunoreactive kallikrein in tumor homogenates was the same as in the pancreas. Kallikrein in tumor cells exists as a proenzyme and is released into blood in high concentrations. The impact of the presence of a kallikrein-producing tumor on other kallikrein-containing organs and other possibly interrelated systems was investigated. The concentration of kallikrein in the submandibular gland and pancreas of host rats was not significantly different from that of control rats. Urinary kallikrein secretion was significantly increased, although this may be a result of the high plasma glandular kallikrein concentration combined with kidney damage. The plasma concentration of kininogen, kininase, and renin was not significantly different from control rats. Rats with tumor had significantly lower blood pressure than did control animals, and blood pressure was inversely related to the concentration of glandular kallikrein in plasma. However, it was not proven that the low blood pressure was due to the high concentration of kallikrein. Nephrectomized tumor rats gave a smaller hypotensive response to kininase inhibition than was expected from their high concentration of circulating kallikrein. This may be explained by the absence of the "free kallikrein" fraction in plasma of host rats.

Amylases↗
PubMed1985

Ductal metaplasia of human exocrine pancreas and its association with carcinoma.

Monoclonal antibodies to cell surface markers of human exocrine pancreas were used to establish the cytotypic expression of cells forming "tubular complexes" in pancreases from six adults without carcinoma and in the nontumorous pancreatic parenchyma of 16 pancreases with carcinoma. These cells manifested duct cell determinants. In general, the presence of cells with duct cell surface markers within the acini corresponded to the normal distribution of centroacinar cells in the 30 control human pancreases (from cadaveric donors); however, foci of abnormal acini were seen in these pancreases independent of or intermingled with the "tubular complexes." The acini in these abnormal areas were formed by a core of cells and cell processes that expressed duct cell determinants. They were partially surrounded by acinar cells and showed slight or no lumenal dilation. While the causative agent(s), the cell(s) of origin, and the regression and/or progression of these lesions are yet to be determined, the replacement of acini by the spectrum of lesions composed of cells with duct cell surface marker is suggested to constitute ductal metaplasia.

Animals↗
PubMed1984

Properties of purified carnitine acyltransferases of mouse liver peroxisomes.

The purpose of this study was to characterize the physical, kinetic, and immunological properties of carnitine acyltransferases purified from mouse liver peroxisomes. Peroxisomal carnitine octanoyltransferase and carnitine acetyltransferase were purified to apparent homogeneity from livers of mice fed a diet containing the hypolipidemic drug Wy-14,643 [( 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]-acetic acid). Both enzymes have a molecular weight of 60,000 and a similar pH optimum. Carnitine octanoyltransferase had a maximum activity for C6 moieties while the maximum for carnitine acetyltransferase was with C3 and C4 moieties. The apparent Km values were between 2 and 20 microM for the preferred acyl-CoA substrates, and the Km values for L-carnitine varied depending on the acyl-CoA cosubstrates used. The Hill coefficient, n, was approximately 1 for all acyl-CoAs tested, indicating Michaelis-Menten kinetics. Carnitine octanoyltransferase retained its maximum activity when preincubated with 5,5'-dithiobis-(2-nitrobenzoate) at pH 7.0 or 8.5. Neither carnitine octanoyltransferase nor carnitine acetyltransferase were inhibited by malonyl-CoA. The immunology of carnitine octanoyltransferase is discussed. These data indicate that peroxisomal carnitine octanoyltransferase and carnitine acetyltransferase function in vivo in the direction of acylcarnitine formation, and suggest that the concentration of L-carnitine could influence the specificity for different acyl-CoA substrates.

Acetyltransferases↗
PubMed1984

Irreversible inhibition of hepatic glutathione S-transferase by ciprofibrate, a peroxisome proliferator.

Ciprofibrate (2-[4-(2,2-dichlorocyclopropyl) phenoxy]2-methyl propionic acid) which is a hypolipidemic agent and has been shown to cause peroxisome proliferation, non-competitively inhibits glutathione S-transferase activity of rat liver, both in vivo and in vitro. Among all the glutathione S-transferases of rat liver, ligandin is maximally inhibited by ciprofibrate. Studies with the purified glutathione S-transferases of rat liver indicate that the affinities of different subunits of liver enzymes for ciprofibrate are in the order Ya greater than Yb, Yb' greater than Yc.

Animals↗
PubMed1984

Peroxisome-associated enzymes and serum lipids in tumour-bearing rats treated with peroxisome-proliferating agents.

Xenobiotic induction of liver peroxisomes is associated with hypolipidemia. To test the involvement of the peroxisome proliferation with the hypolipidemia, male rats were inoculated in the groin with five different tumors: an aflatoxin-induced hepatoma, a lasiocarpine-induced hepatoma, an actinomycin-D-induced mesothelioma, a lasiocarpine-induced squamous cell carcinoma, and a methylnitrosourea-induced fibrosarcoma. After the tumours reached a suitable size, the rats were fed diets containing the peroxisome-proliferating hypolipidemic agents tibric acid (2-chloro-5-[3,5-dimethylpiperidinosulfonyl] benzoic acid) or Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid) for 2 weeks. Liver and tumor tissues were then assayed for the peroxisome-associated enzymes, catalase and carnitine acetyltransferase, and correlated with serum levels of triglyceride and cholesterol. The presence of the tumors caused a predictable decrease in liver catalase and a slight elevation of liver carnitine acetyltransferase. Serum cholesterol was elevated slightly, while serum triglyceride levels were elevated, unchanged, or decreased in the tumor-bearing rats maintained on control diet. Inclusion of the xenobiotics in the diet caused increases in liver weight, catalase, and carnitine acetyltransferase. Serum triglycerides were decreased in the three groups which were not already decreased, but a decrease in serum cholesterol was only found in one group after only one of the treatments. The latter finding demonstrates that peroxisomal enzyme induction can be dissociated from the decrease in serum cholesterol. The data were further evaluated by testing for correlations between the changes in these components, comparing changes within groups and between groups. These correlations indicate an inverse biological association between liver catalase and serum cholesterol and between liver carnitine acetyltransferase and serum triglyceride. The latter correlation was inverse only for comparisons between groups, suggesting that carnitine acetyltransferase activity is associated with serum triglycerides only during the perturbational state.

Acetyltransferases↗
PubMed1984

Effect of hypolipidemic peroxisome proliferators on unscheduled DNA synthesis in cultured hepatocytes and on mutagenesis in Salmonella.

The peroxisome proliferators Wy-14,643, BR-931, nafenopin and ciprofibrate were tested in the primary hepatocyte culture-unscheduled DNA synthesis assay and in the Ames Salmonella microsome mutagenicity assay. The amount of unscheduled DNA synthesis (UDS) in hepatocytes was determined by quantifying the amount of [3H]thymidine incorporated into DNA in the presence of hydroxyurea after isolation of nuclei from hepatocytes treated with the test agent. Wy-14,643 and BR-931 induced unscheduled DNA synthesis in rat hepatocytes, whereas nafenopin and ciprofibrate had no effect. All of the peroxisome proliferators were negative in the Ames Salmonella assay.

Animals↗
PubMed1984

DNA damage related to increased hydrogen peroxide generation by hypolipidemic drug-induced liver peroxisomes.

Several hypolipidemic drugs and certain industrial plasticizers induce proliferation of peroxisomes, enhance the activity of peroxisome-associated beta-oxidation of fatty acids, and produce hepatocellular carcinomas in the livers of rodents. Because these chemicals themselves are not mutagens and do not covalently modify DNA, unlike the majority of chemical carcinogens, we proposed that the persistent proliferation of peroxisomes, and the induction of associated peroxisomal oxidases, caused a sustained increase in intracellular H2O2 or other reduced oxygen species, which would then introduce mutagenic DNA damage. In the present study, we investigated the ability of peroxisomes purified from the livers of normal and hypolipidemic drug-treated rats to induce DNA strand scission in vitro. Gradient-purified peroxisomes from livers of hypolipidemic drug-treated rats produced a 30- to 70-fold increase in H2O2 generation when compared to controls. The levels of H2O2 generated in incubations containing control or hypolipidemic drug-induced peroxisomes correlated well with the induction of single strand breaks in supercoiled simian virus 40 DNA molecules that were included in these reconstituted peroxisome incubations. Addition of excess catalase to peroxisome incubations failed to prevent strand breaks, suggesting that other reduced oxygen species may be rapidly generated from H2O2. These experimental results are consistent with a mechanism of hepatocarcinogenesis in which hepatocellular genetic damage is introduced by the by-products of peroxisomal fatty acid beta-oxidation, an oxidative pathway that is dramatically increased in hypolipidemic drug-treated livers.

Animals↗
PubMed1984

Induction and origin of hepatocytes in rat pancreas.

2-[4(2,2- Dichlorocyclopropyl )phenoxy]2-methyl propionic acid (ciprofibrate), a peroxisome proliferator , induced hepatocytes in the pancreas of adult male F-344 rats when added to their diet at a dosage of 10 mg/kg body weight for 60-72 wk. These cells are morphologically indistinguishable from hepatic hepatocytes and were usually localized adjacent to islets of Langerhans with extensions into surrounding acinar tissue. A significant increase in the volume density of peroxisomes, together with immunochemically detectable amounts of two peroxisome-associated enzymes, was observed in pancreas with hepatocytes of rats maintained on ciprofibrate. Uricase-containing crystalloid nucleoids, specific for rat hepatocyte peroxisomes, were present in pancreatic hepatocytes. These structures facilitated the identification of cells with hybrid cytoplasmic features characteristic of pancreatic acinar and endocrine cells and hepatocytes. Such cells are presumed to represent a transitional state in which pancreas specific genes are being repressed while liver specific ones are simultaneously expressed. The presence of exocrine and/or endocrine secretory granules in transitional cells indicates that acinar/intermediate cells represent the precursor cell from which pancreatic hepatocytes are derived.

Animals↗
PubMed1984

Alteration of a membrane associated marker in transplantable rat pancreatic acinar cell carcinoma.

A monoclonal murine IgG has been developed which detects a cellular and intracytoplasmic membrane marker expressed only in the rat pancreatic acinar cell. Membrane aberrations in chemically induced transplantable rat pancreas acinar cell adenoma and carcinoma were examined using this IgG. The presence of this membrane marker was assessed by indirect immunofluorescence using paraffin sections of normal pancreas, acinar cell adenoma and transplanted tumors from rats and nude mice. The intracytoplasmic membrane of cells in acinar cell adenoma revealed a much higher intensity of fluorescence compared with normal acinar cells. In contrast there was an almost complete absence of fluorescent staining of the intracytoplasmic membranes of acinar cell carcinoma while their cell membranes showed an intensity of fluorescence far exceeding that of normal acinar cells. These findings suggest a defect in the dynamics of membrane-associated antigen(s) in these cancer cells.

Adenoma↗
PubMed1984

Response of hepatocytes transplanted into syngeneic hosts and heterotransplanted into athymic nude mice to peroxisome proliferators.

The development of a transplantation system by which rat hepatocytes can be implanted and remain viable in the dorsal fascia of two-thirds hepatectomized syngeneic hosts provides an opportunity to examine whether such transplanted hepatocytes retain the capacity to recognize and respond to the peroxisome proliferators 2-[4-(2,2- dichlorocyclopropyl )phenoxy]-2- methylpropionic acid (ciprofibrate), a hypolipidemic drug, and di-(2-ethylhexyl)phthalate (DEHP), an industrial plasticizer. Male F344 rats with transplanted rat hepatocytes were fed a control diet or a diet containing either 0.05% ciprofibrate (w/w) or 2% DEHP (v/w). After 4 weeks, the animals were sacrificed, and transplanted hepatocytes revealed a significant increase in the numerical density of peroxisomes in both ciprofibrate- and DEHP-fed rats. The volume density of peroxisomes in transplanted hepatocytes increased 9.2- and 5.3-fold, respectively, in ciprofibrate- and DEHP-fed rats, whereas the volume density of mitochondria remained essentially unchanged. The magnitude of increase in peroxisome volume density in transplanted hepatocytes was comparable to increases in the volume density of these organelles in the liver parenchymal cells of syngeneic hosts. The present study also demonstrates that hepatocytes isolated from cat liver and heterotransplanted into partially hepatectomized athymic nude mice retain their biological integrity and respond to the peroxisome proliferative effect of ciprofibrate. This observation suggests the possibility that hepatocytes obtained from small segments of liver of humans, primates, and other species and heterotransplanted into nude mice might provide a valuable model system for toxicological evaluation of chemicals. These studies suggest that hepatocytes, irrespective of their location in the body, recognize the peroxisome proliferator or its active metabolite(s), which stimulates the expression of peroxisome-specific genes in these cells.

Animals↗
PubMed1984

Immunocytochemical localization of exocrine enzymes in rat pancreatic acinar carcinoma.

Ten pancreatic secretory proteins have been demonstrated in differentiated pancreatic acinar carcinoma cells by the protein A-gold immunocytochemical approach. The high resolution of the technique has allowed for the localization of the different proteins in the cellular compartments involved in protein secretion: RER, Golgi and secretory granules. The quantitative evaluation of the labeling for amylase has demonstrated the presence of an increasing gradient in the intensity from the RER to the Golgi and to the secretory granules which may reflect the process of protein concentration along the secretory pathway. These results, together with those obtained using the pulse-labeling autoradiographic approach, demonstrate that differentiated acinar carcinoma cells are capable of processing secretory proteins. When intensities of labeling obtained for different proteins on acinar carcinoma cells were compared to those obtained on normal pancreatic acinar cells, major differences were observed for some proteins. In addition, studies performed on the pancreatic tissue of the tumor-bearing animals have shown the presence of morphological alterations in the acinar cells.

Animals↗
PubMed1984

Studies of pancreatic carcinogenesis in different animal models.

Pancreatic carcinomas can be induced in rat, guinea pig and hamster by a variety of carcinogens. The types of neoplasms which arise vary with the species of rodent. In the rat, they consist exclusively of acinar cells, in the other species the lesions are adenocarcinomas resembling those derived from pancreatic ductules and ducts, those in hamster more so than in guinea pigs. Careful sequential studies in the guinea pig and hamster suggest that acinar cells together with ductular and duct cells are involved in the genesis of duct adenocarcinomas. In each rodent model, the acinar cell appears to be quite sensitive to continued exposure to carcinogen. In each instance, acini undergo modulation, and in the guinea pig and hamster, permanent metaplastic transformation to ductlike structures. Such cells assume an enhanced capacity for cell proliferation which persists following cessation of carcinogen treatment. Other studies suggest that adult pancreatic acinar cells possess a surprising degree of plasticity. Their involvement in the pathogenesis of neoplasms resembling pancreatic ducts is not unlike other carcinogenic sequences where extensive cell modulation and metaplasia precede and are an integral part of the neoplastic transformation.

Adenoma↗