- Email: [email protected]
Effect of quinolinic acid administration on rat liver: Ultrastructural investigation
Exp Toxic Patho11995; 47: 375-379 Gustav Fischer Verlag Jena
Medical Centre of Postgraduate Education Laboratory of Histochemistry, Warsaw, Poland
Effect of quinolinic acid administration on rat liver: Ultrastructural investigation M. BESKID, E. ZAMECKA, H. DYBKOWSKA-KLos, J. JACHIMOWICZ, w. KOCJASZ With 3 figures Received: July 8, 1994; Revised: October 9, 1994; Accepted: October 25, 1994 Address for correspondence: Prof. M. BESKID, M. D., DSc., Laboratory of Histochemistry, Marymoncka 99, 01-813 Warsaw, Poland. Key words: Quinolinic acid; Liver, qinolinic acid; Biotransformation, quinolinic acid.
Summary Quinolinic acid was administered intraperitoneally in a dose of 30 or 60 mmol, once every 24 h for 8 days. Its result in the dose of 30 mmol was the proliferation of smooth elements of the endoplasmic reticulum. The use of quinolinic acid in a dose of 60 mmol was characterized by the presence of more profound damage of organelles, among them the distinct decrease of the rough elements of the endoplasmic reticulum and polyribosomal structures was seen, and moreover, wide areas devoid of organelles were observed.
Introduction Quinolinic acid is an end product of tryptophan metabolism arisen via the kynurenine pathway. It hat already been known to be present in the liver and kidney as well as in the brain (WOLFENBERGER et al. 1983; MORONI et al. 1984; GHOLSON et al. 1964). It has been reported that quinolinic acid caused an inhibition of gluconeogenesis in the liver (VENEZIALE et al. 1967; McDANIEL et al. 1972; GABBAY 1985), as well as in the kidney (KLAHR and SCHOOLWERTH 1972). Moreover, it was shown that this inhibition could be reversed by the administration of mangan ions (McDANIEL et al. 1972; VENEZIALE et al. 1967; SPYDERVOLD et al. 1974). This compound is also an inhibitor of a number of aminotransferase enzymes (TOBES and MASON 1975), especially aspartate aminotransferase (Hsu and FAHIEN 1976). It also causes a massive accumulation of the intermediates of the tricarboxylic acid cycle in the liver tissue (SPYDERVOLD et al. 1974; GABBA Y 1985). Metabolite and flux data suggest an increase in the rate of lipogenesis in quinolinic acid treated rats with the decrease of long chain acyl CoAs (SPYDERVOLD et al. 1974). Quinolinic acid readily chelates mangan ions (VENEZIALE et al. 1967; McDANIEL et al. 1972;
SPYDERVOLD et al. 1974), as well as calcium ions (BESKID et al. 1991 ab). Hence, it may be noted that metabolic disturbances caused by quinolinic acid have been explored with great interest, but much less in the morphological consequences. Thus, it supports our explanation of quinolinic acid effect on the ultrastructural image of the liver cells.
Material and methods Male Wistar rats, 200-220 g in weight, were used for study. The animals were divided in 3 groups, two experimental and one control, each group consisted of 8 rats. Quinolinic acid (Sigma) as mixture in saline solution was injected intraperitoneally once daily for 8 days. A volume of 1 ml of saline solution contained 30 or 60 mmol of quinolinic acid. Control animals in the same way were given 1 ml of saline solution once daily for 8 days. Material for electron microscopic examination as fresh tissue was taken from the right lobe of the liver, fixed in buffered glutaraldehyde solution and then in osmium tetrooxide according to PALADE (1952). After dehydration, the tissue material was embedded in Epon 812 according to LUFf (1961). Ultrathin sections were stained with uranyl acetate and lead citrate according to REYNOLDS (1963). The material was examined in a JEM 100 B electron microscope.
Results Ultrastructurally, it was found that when quinolinic acid was administered in a dose of 30 mmol significant results of this treatment were the changes mainly concerning the endoplasmic reticulum structures, in much less degree relating to the mitochondria. In these cases the proliferation signs of smooth endoplasmic reticulum Exp Toxic Pathol47 (1995) 5
375
376
Exp Toxic Patho147 (1995) 5
Fig. 1. Quinolinic acid - 30 mmol. Proliferation of smooth endoplasmic reticulum elements. x 6 400. Fig. 2. Quinolinic acid - 60 mmol. Strongly developed nucleolus with accumulation of chromatine material. Nuclear envelope distended. Endoplasmatic reticulum elements dilated. x 24 500. Fig. 3. Quinolinic acid - 60 mmol. Nucleus with marked. condensed nucleolus. Within the cytoplasm - area devoid of organelles. x 35 000.
elements were visible. Then they took the form of the multiple small vesicles, diffusely distributed within the cytoplasm. It may be added that simultaneously a distinct decrease of rough endoplasmic reticulum structures was observed. Mitochondria usually were swollen. Lysosomes small and scarce. The Golgi apparatus was poorly developed (Fig. 1). While quinolinic acid was administered in the dose of 60 mmol the more profound injuries of cytoplasmic organelles as well as of the nucleus were noted. Within the nucleus in some cases the loss of chromatine grains was seen and then a more condense nucleolus could be observed. In other cases strongly developed nucleoli with accumulation of chromatine material around them occupied a notable part of the nucleus (Fig. 2). The nuclear envelope was often distended, forming perinuclearly situated channels and vacuoles. Within the cytoplasm smooth endoplasmic reticulum elements were diffusely distributed, but they as a rule were irregularly dilated, forming channels and cisterns. A marked loss of rough endoplasmic re-
ticulum elements and polirybosomal structures was noted. Mitochondria were swollen, usually united and had incompletely or completely blurred outlines of cristae. Lysosomes were small and single. Lipid droplets were numerous. The Golgi apparatus was poorly developed. Moreover within the cytoplasm wide areas devoid of organelles were noted (Fig. 3).
Discussion Electron-microscopic findings have shown that a proliferation of smooth endoplasmic elements is characteristic for the smaller dose of quinolinic acid administration. This accounted for an ultrastructural equivalent of microsomal enzymatic induction (CONNEY 1976; 1986). It was found that the activities of drug metabolizing enzymes in liver microsomes are markedly increased when animals are treated with various drugs, toxic substances, as well as normal body constituents (CONNEY 1967; Exp Toxic Pathol47 (1995) 5
377
1986; WILLIAMS 1975; GILLETE 1975; MANNERING 1975). This increase in activity appears to represent an enlarged concentration of enzyme protein and is referred to as "enzyme induction" (CONNEY 1967). It has been demonstrated that the enzymes responsible for the synthesis and degradation of quinolinic acid, had been identified and characterized both in peripheral tissues (NISHIZUKA and HAYAISHI 1963; GHOLSON et al. 1964; HAGINO et al. 1968; WOLF 1974), and in the brain (GAL et al. 1966; FOSTER et al. 1985; WHETSELL et aI. 1988). The enzymes participated in the metabolic pathway of tryptophan as tryptophan pyrrolase (or tryptophan 2, 3-dioxygenase), as well as that produced quinolinic acid (3-hydroxyanthranilic acid oxygenase), and as the catabolic enzyme (quinolinic acid phosphoribosyltransferase) are adaptatively controlled by their own substrate (WOLF 1974; STONE and CONNICK 1985; FOSTER et al. 1985; WHETSELL et al. 1988). That quinolinic acid can produce the proliferation of endoplasmic reticulum smooth elements within the liver cells may be accounted to be enzymatic inductor. Although, it is interesting to note that quinolinic acid administered in a higher dose resulted in marked decrease of rough elements of the endoplasmic reticulum as well as polyribosomal structures. Moreover, within the cytoplasm wide areas devoid of organelles were noted. This observation may result from the decreasing effect of quinolinic acid on RNA and protein synthesis. Quinolonic acid is condensed with 5-phosphoribosylI-pyrophosphate to from nicotinic acid ribonucleotide by the enzyme quinolinate transphosphoribosylase. This enzyme is either responsible for both the condensation and decarboxylation reactions (WOLF 1974; NISHIZUKA and HAYAISHI 1963; HAGINO et al. 1968; GHOLOSON et al. 1964). It may be taken into consideration that manifold administration of quinolinic acid can lead to its greatest level within tissue. Although quinolinic acid hardly penetrated into the cells, including the liver cells (IJICHI et aI. 1966; LAN and HENDERSON 1968), it is possible that the biotransformation of quinolinic acid will be required to raise the PP-ribose-P content. This may induce an increased demand for PP-ribose-P for quinolinic acid metabolism and hence produce the decrease of purine and pyrimidine nucleoside monophosphate synthesis. Both purine and pyrimidine bases for nucleoside monophosphate synthesis require PP-ribose-P. As the rate-limiting steps of both purine and pyrimidine nucleotide synthesis are controlled by the PP-ribose-P concentration in the cell (HOLMES 1978; KEpPLER and HOLSTEGE 1982; SWAIN and HOLMES 1986). It may be reflected in some limits by the presence of the decreasing effect of quinolinic acid administration on xylulose-5-phosphate content as hepatic metabolite in the quinolinic acid treated rats (SPYDERVOLDetal. 1974). Thus, rates of synthesis of both purine and pyrimidine nucleotides are dependent on the availability of PPribose-P in the cell, and this may coordinate the produc378
Exp Toxic Patho147 (1995) 5
tion of these two classes of ribonucleotides. It follows that depletion of PP-ribose-P may lead to a decrease in the rate of both purine and pyrimidine synthesis in the cell. It should be added that after quinolinic acid excitoxic lesions in the rat striatum or hippocampus, the enzymic activity increases, both the enzyme producing, as well as that breaks it down (FOSTER ET AL. 1985; SPECIALE et al. 1987). It may be conluded that quinolinic acid in a smaller dose produced the proliferation of smooth elements of the endoplasmic reticulum appeared to be inductor of the biotransformation, but in higher dose can produce the inhibition of the RNA and protein synthesis, which are ultrastructurally manifested by the decrease of rough elements of the endoplasmic reticulum, polyribosomal structures, and by the presence of the wide areas devoid of organelles.
References BESKID M, FINKIEWICZ-MURAWIEJSKA L, OBMINSKI Z et al.: Quinolinic acid: a modulator of the heart calcium channel in the rat and a binder of calcium ions. Exp Pathol 1991a; 41: 110-114. BESKID M, FINKIEWICZ-MURAWIEJSKA L, OBMINSKI Z et al.: Quinolinic acid: effect on 45 Ca content in perfused rat heart preparations and its calcium ion binding property in Krebs-Henseleit medium and blood serum. Exp Pathol 1991b;42: 175-178. CONNEY AH: Pharmacological implications of microsomal enzyme induction. Pharmacol Rev 1967; 19: 317-366. CONNEY AH: Induction of microsomal cytochrome P-450 enzymes: the first Bernard B Brodie lecture at Pennsylvania State University. Life Science 1986; 39: 2493-2518. FOSTER DO, WHETSELL WO JR, BIRD ED et al.: Quinolinic acid phosphoribosyltransferase in human and rat brain: activity in Huntington's disease and in quinolinate -lesioned rat striatum. Brain Res 1985; 336: 207-214. GABBAY RA: Quinolinate inhibition of gluconeogenesis is dependent on cytosolic oxalacetate concentration. FEBS 1985; 189: 367-372. . GHOLSON RK, UEDA I, OGASAWARA N, et al.: The enzymatic conversion to nicotinic acid mononucleotide in mammalian liver. J BioI Chern 1964; 239: 1208-1214. GILLETTE JR: Pharmacological and toxicological aspects of drug interaction. In: Drugs ant the liver. Arzneimittel und Leber. III Int. Symp. 12.-14. Oktober 1973 Freiburg i. Br. Schattauer Verlag Stuttgart-New York 1975 pp. 119-142. HAGINO Y, LAN SJ, NG CY, et al.: Metabolism of pyridinium precursors of pyridine nucleotides in perfused rat liver. J BioI Chem 1968; 243: 4980-4986. Hsu SL, FAHIEN LA: Effect of quinolinate on aminotransferases Arch Biochem Biophys 1976; 177: 217-225. HOLMES EW: Regulation of biosynthesis de novo. In: KELLEY WN, WEINER 1M (Eds.): Uric acid. Springer-Verlag Berlin Heidelberg New York 1978 pp. 21-42. IJICHI H, ICHIY AMA A, HAYAISHI 0 : Studies on the biosyn-
thesis of nicotinamide adenine dinucleotide. J BioI Chern 1966;241: 3701-3707. KEpPLER D, HOLSTEGE A: Pyrimidine nucleotide metabolism and its compartmentation. In: SIES H (Ed.): Metabolic compartmentation. Ac. Press Orlando 1982 pp. 147-203. KLAHR S, SCHOOLWERTH AC: Renal gluconeogenesis. Effects of quinolinic acid. Biochim Biophys Acta 1972; 279: 157-162. LAN SJ, HENDERSON LM: Uptake of nicotinic acid and nicotinamide by rat erythrocytes. J BioI Chern 1968; 243: 3388-3394. LUff JH: Improvements in epoxy resin embedding methods. J Biophys Biochem Cytol1961; 9: 409. McDANIEL HG, REDDY WJ, BOSHELL BR: The mechanism of inhibition of phosphoenolpyruvate carboxylase by quinolinic acid. Biochim Biophys Acta 1972; 276: 543-550. MORONIF, LOMBARDI G, CARLA V, et al.: The excitotoxin quinolinic acid is present and unevenly distributed in the rat brain. Brain Res 1984; 295: 352-355. NISHIZUKA Y , HAY AISHI 0: Studies on the biosynthesis of nicotinamide adenine dinucleotide. J BioI Chern 1963; 238: 3369-3377. STONE TW, CONNICK JH: Quinolinic acid and other kynurenines in the central nervous system. Neurosci 1985; 15: 597-617.
SPECIALE C, OKUNO E, SCHWARCZ R: Increased quinolinic acid metabolism following neuronal degeneration in the rat hippocampus. Brain Res 1987; 436: 18-24. SPYDERVOLD OS, ZAHEER-BAQUER N, McLEAN P, et al.: The effect of quinolinic acid on the content and distribution of hepatic metabolites. Arch Biochem Biophys 1974; 164: 590-601. SWAIN JL, HOLMES EW: Nucleotide metabolism in cardiac muscle. In: FOZZARD HV et al. (Eds.): The heart and cardiovasculat system. Raven Press New York 1986 pp. 911-929. TOBES MC, MASON M: L-Kynurenine aminotransferase and L-alpha-aminoadipate aminotransferase. Evidence for identity. Biochem Biophys Res Commun 1975; 62: 390-397. VENEZIALE CM, WALTER P, KNEER N, et al.: Influnce of 1tryptophan and its metabolites on gluconeogenesis in the isolated, perfused liver. Biochem 1967; 6: 2129-2138. WILLIAMS RT: Chemistry of detoxication. In: Drugs and the liver. Arzneimittel und Leber. III Int. Symp. 12.-14. Oktober 1973, Freiburg i. Br. Schattauer Verlag StuttgartN.York 1975 pp. 51-64. WOLF H: Studies of tryptophan metabolism in man. Scand J Clin Lab Invest 1974; suppl. 136; 33: 13-34. WOLFENSBERGER A, AMSLER H, CUENOD M, et al.: Identification of quinolinic acid in rat and human brain tissue. Neurosci Lett 1983; 41: 247-254.
Exp Toxic Pathol47 (1995) 5
379
Medical Centre of Postgraduate Education Laboratory of Histochemistry, Warsaw, Poland
Effect of quinolinic acid administration on rat liver: Ultrastructural investigation M. BESKID, E. ZAMECKA, H. DYBKOWSKA-KLos, J. JACHIMOWICZ, w. KOCJASZ With 3 figures Received: July 8, 1994; Revised: October 9, 1994; Accepted: October 25, 1994 Address for correspondence: Prof. M. BESKID, M. D., DSc., Laboratory of Histochemistry, Marymoncka 99, 01-813 Warsaw, Poland. Key words: Quinolinic acid; Liver, qinolinic acid; Biotransformation, quinolinic acid.
Summary Quinolinic acid was administered intraperitoneally in a dose of 30 or 60 mmol, once every 24 h for 8 days. Its result in the dose of 30 mmol was the proliferation of smooth elements of the endoplasmic reticulum. The use of quinolinic acid in a dose of 60 mmol was characterized by the presence of more profound damage of organelles, among them the distinct decrease of the rough elements of the endoplasmic reticulum and polyribosomal structures was seen, and moreover, wide areas devoid of organelles were observed.
Introduction Quinolinic acid is an end product of tryptophan metabolism arisen via the kynurenine pathway. It hat already been known to be present in the liver and kidney as well as in the brain (WOLFENBERGER et al. 1983; MORONI et al. 1984; GHOLSON et al. 1964). It has been reported that quinolinic acid caused an inhibition of gluconeogenesis in the liver (VENEZIALE et al. 1967; McDANIEL et al. 1972; GABBAY 1985), as well as in the kidney (KLAHR and SCHOOLWERTH 1972). Moreover, it was shown that this inhibition could be reversed by the administration of mangan ions (McDANIEL et al. 1972; VENEZIALE et al. 1967; SPYDERVOLD et al. 1974). This compound is also an inhibitor of a number of aminotransferase enzymes (TOBES and MASON 1975), especially aspartate aminotransferase (Hsu and FAHIEN 1976). It also causes a massive accumulation of the intermediates of the tricarboxylic acid cycle in the liver tissue (SPYDERVOLD et al. 1974; GABBA Y 1985). Metabolite and flux data suggest an increase in the rate of lipogenesis in quinolinic acid treated rats with the decrease of long chain acyl CoAs (SPYDERVOLD et al. 1974). Quinolinic acid readily chelates mangan ions (VENEZIALE et al. 1967; McDANIEL et al. 1972;
SPYDERVOLD et al. 1974), as well as calcium ions (BESKID et al. 1991 ab). Hence, it may be noted that metabolic disturbances caused by quinolinic acid have been explored with great interest, but much less in the morphological consequences. Thus, it supports our explanation of quinolinic acid effect on the ultrastructural image of the liver cells.
Material and methods Male Wistar rats, 200-220 g in weight, were used for study. The animals were divided in 3 groups, two experimental and one control, each group consisted of 8 rats. Quinolinic acid (Sigma) as mixture in saline solution was injected intraperitoneally once daily for 8 days. A volume of 1 ml of saline solution contained 30 or 60 mmol of quinolinic acid. Control animals in the same way were given 1 ml of saline solution once daily for 8 days. Material for electron microscopic examination as fresh tissue was taken from the right lobe of the liver, fixed in buffered glutaraldehyde solution and then in osmium tetrooxide according to PALADE (1952). After dehydration, the tissue material was embedded in Epon 812 according to LUFf (1961). Ultrathin sections were stained with uranyl acetate and lead citrate according to REYNOLDS (1963). The material was examined in a JEM 100 B electron microscope.
Results Ultrastructurally, it was found that when quinolinic acid was administered in a dose of 30 mmol significant results of this treatment were the changes mainly concerning the endoplasmic reticulum structures, in much less degree relating to the mitochondria. In these cases the proliferation signs of smooth endoplasmic reticulum Exp Toxic Pathol47 (1995) 5
375
376
Exp Toxic Patho147 (1995) 5
Fig. 1. Quinolinic acid - 30 mmol. Proliferation of smooth endoplasmic reticulum elements. x 6 400. Fig. 2. Quinolinic acid - 60 mmol. Strongly developed nucleolus with accumulation of chromatine material. Nuclear envelope distended. Endoplasmatic reticulum elements dilated. x 24 500. Fig. 3. Quinolinic acid - 60 mmol. Nucleus with marked. condensed nucleolus. Within the cytoplasm - area devoid of organelles. x 35 000.
elements were visible. Then they took the form of the multiple small vesicles, diffusely distributed within the cytoplasm. It may be added that simultaneously a distinct decrease of rough endoplasmic reticulum structures was observed. Mitochondria usually were swollen. Lysosomes small and scarce. The Golgi apparatus was poorly developed (Fig. 1). While quinolinic acid was administered in the dose of 60 mmol the more profound injuries of cytoplasmic organelles as well as of the nucleus were noted. Within the nucleus in some cases the loss of chromatine grains was seen and then a more condense nucleolus could be observed. In other cases strongly developed nucleoli with accumulation of chromatine material around them occupied a notable part of the nucleus (Fig. 2). The nuclear envelope was often distended, forming perinuclearly situated channels and vacuoles. Within the cytoplasm smooth endoplasmic reticulum elements were diffusely distributed, but they as a rule were irregularly dilated, forming channels and cisterns. A marked loss of rough endoplasmic re-
ticulum elements and polirybosomal structures was noted. Mitochondria were swollen, usually united and had incompletely or completely blurred outlines of cristae. Lysosomes were small and single. Lipid droplets were numerous. The Golgi apparatus was poorly developed. Moreover within the cytoplasm wide areas devoid of organelles were noted (Fig. 3).
Discussion Electron-microscopic findings have shown that a proliferation of smooth endoplasmic elements is characteristic for the smaller dose of quinolinic acid administration. This accounted for an ultrastructural equivalent of microsomal enzymatic induction (CONNEY 1976; 1986). It was found that the activities of drug metabolizing enzymes in liver microsomes are markedly increased when animals are treated with various drugs, toxic substances, as well as normal body constituents (CONNEY 1967; Exp Toxic Pathol47 (1995) 5
377
1986; WILLIAMS 1975; GILLETE 1975; MANNERING 1975). This increase in activity appears to represent an enlarged concentration of enzyme protein and is referred to as "enzyme induction" (CONNEY 1967). It has been demonstrated that the enzymes responsible for the synthesis and degradation of quinolinic acid, had been identified and characterized both in peripheral tissues (NISHIZUKA and HAYAISHI 1963; GHOLSON et al. 1964; HAGINO et al. 1968; WOLF 1974), and in the brain (GAL et al. 1966; FOSTER et al. 1985; WHETSELL et aI. 1988). The enzymes participated in the metabolic pathway of tryptophan as tryptophan pyrrolase (or tryptophan 2, 3-dioxygenase), as well as that produced quinolinic acid (3-hydroxyanthranilic acid oxygenase), and as the catabolic enzyme (quinolinic acid phosphoribosyltransferase) are adaptatively controlled by their own substrate (WOLF 1974; STONE and CONNICK 1985; FOSTER et al. 1985; WHETSELL et al. 1988). That quinolinic acid can produce the proliferation of endoplasmic reticulum smooth elements within the liver cells may be accounted to be enzymatic inductor. Although, it is interesting to note that quinolinic acid administered in a higher dose resulted in marked decrease of rough elements of the endoplasmic reticulum as well as polyribosomal structures. Moreover, within the cytoplasm wide areas devoid of organelles were noted. This observation may result from the decreasing effect of quinolinic acid on RNA and protein synthesis. Quinolonic acid is condensed with 5-phosphoribosylI-pyrophosphate to from nicotinic acid ribonucleotide by the enzyme quinolinate transphosphoribosylase. This enzyme is either responsible for both the condensation and decarboxylation reactions (WOLF 1974; NISHIZUKA and HAYAISHI 1963; HAGINO et al. 1968; GHOLOSON et al. 1964). It may be taken into consideration that manifold administration of quinolinic acid can lead to its greatest level within tissue. Although quinolinic acid hardly penetrated into the cells, including the liver cells (IJICHI et aI. 1966; LAN and HENDERSON 1968), it is possible that the biotransformation of quinolinic acid will be required to raise the PP-ribose-P content. This may induce an increased demand for PP-ribose-P for quinolinic acid metabolism and hence produce the decrease of purine and pyrimidine nucleoside monophosphate synthesis. Both purine and pyrimidine bases for nucleoside monophosphate synthesis require PP-ribose-P. As the rate-limiting steps of both purine and pyrimidine nucleotide synthesis are controlled by the PP-ribose-P concentration in the cell (HOLMES 1978; KEpPLER and HOLSTEGE 1982; SWAIN and HOLMES 1986). It may be reflected in some limits by the presence of the decreasing effect of quinolinic acid administration on xylulose-5-phosphate content as hepatic metabolite in the quinolinic acid treated rats (SPYDERVOLDetal. 1974). Thus, rates of synthesis of both purine and pyrimidine nucleotides are dependent on the availability of PPribose-P in the cell, and this may coordinate the produc378
Exp Toxic Patho147 (1995) 5
tion of these two classes of ribonucleotides. It follows that depletion of PP-ribose-P may lead to a decrease in the rate of both purine and pyrimidine synthesis in the cell. It should be added that after quinolinic acid excitoxic lesions in the rat striatum or hippocampus, the enzymic activity increases, both the enzyme producing, as well as that breaks it down (FOSTER ET AL. 1985; SPECIALE et al. 1987). It may be conluded that quinolinic acid in a smaller dose produced the proliferation of smooth elements of the endoplasmic reticulum appeared to be inductor of the biotransformation, but in higher dose can produce the inhibition of the RNA and protein synthesis, which are ultrastructurally manifested by the decrease of rough elements of the endoplasmic reticulum, polyribosomal structures, and by the presence of the wide areas devoid of organelles.
References BESKID M, FINKIEWICZ-MURAWIEJSKA L, OBMINSKI Z et al.: Quinolinic acid: a modulator of the heart calcium channel in the rat and a binder of calcium ions. Exp Pathol 1991a; 41: 110-114. BESKID M, FINKIEWICZ-MURAWIEJSKA L, OBMINSKI Z et al.: Quinolinic acid: effect on 45 Ca content in perfused rat heart preparations and its calcium ion binding property in Krebs-Henseleit medium and blood serum. Exp Pathol 1991b;42: 175-178. CONNEY AH: Pharmacological implications of microsomal enzyme induction. Pharmacol Rev 1967; 19: 317-366. CONNEY AH: Induction of microsomal cytochrome P-450 enzymes: the first Bernard B Brodie lecture at Pennsylvania State University. Life Science 1986; 39: 2493-2518. FOSTER DO, WHETSELL WO JR, BIRD ED et al.: Quinolinic acid phosphoribosyltransferase in human and rat brain: activity in Huntington's disease and in quinolinate -lesioned rat striatum. Brain Res 1985; 336: 207-214. GABBAY RA: Quinolinate inhibition of gluconeogenesis is dependent on cytosolic oxalacetate concentration. FEBS 1985; 189: 367-372. . GHOLSON RK, UEDA I, OGASAWARA N, et al.: The enzymatic conversion to nicotinic acid mononucleotide in mammalian liver. J BioI Chern 1964; 239: 1208-1214. GILLETTE JR: Pharmacological and toxicological aspects of drug interaction. In: Drugs ant the liver. Arzneimittel und Leber. III Int. Symp. 12.-14. Oktober 1973 Freiburg i. Br. Schattauer Verlag Stuttgart-New York 1975 pp. 119-142. HAGINO Y, LAN SJ, NG CY, et al.: Metabolism of pyridinium precursors of pyridine nucleotides in perfused rat liver. J BioI Chem 1968; 243: 4980-4986. Hsu SL, FAHIEN LA: Effect of quinolinate on aminotransferases Arch Biochem Biophys 1976; 177: 217-225. HOLMES EW: Regulation of biosynthesis de novo. In: KELLEY WN, WEINER 1M (Eds.): Uric acid. Springer-Verlag Berlin Heidelberg New York 1978 pp. 21-42. IJICHI H, ICHIY AMA A, HAYAISHI 0 : Studies on the biosyn-
thesis of nicotinamide adenine dinucleotide. J BioI Chern 1966;241: 3701-3707. KEpPLER D, HOLSTEGE A: Pyrimidine nucleotide metabolism and its compartmentation. In: SIES H (Ed.): Metabolic compartmentation. Ac. Press Orlando 1982 pp. 147-203. KLAHR S, SCHOOLWERTH AC: Renal gluconeogenesis. Effects of quinolinic acid. Biochim Biophys Acta 1972; 279: 157-162. LAN SJ, HENDERSON LM: Uptake of nicotinic acid and nicotinamide by rat erythrocytes. J BioI Chern 1968; 243: 3388-3394. LUff JH: Improvements in epoxy resin embedding methods. J Biophys Biochem Cytol1961; 9: 409. McDANIEL HG, REDDY WJ, BOSHELL BR: The mechanism of inhibition of phosphoenolpyruvate carboxylase by quinolinic acid. Biochim Biophys Acta 1972; 276: 543-550. MORONIF, LOMBARDI G, CARLA V, et al.: The excitotoxin quinolinic acid is present and unevenly distributed in the rat brain. Brain Res 1984; 295: 352-355. NISHIZUKA Y , HAY AISHI 0: Studies on the biosynthesis of nicotinamide adenine dinucleotide. J BioI Chern 1963; 238: 3369-3377. STONE TW, CONNICK JH: Quinolinic acid and other kynurenines in the central nervous system. Neurosci 1985; 15: 597-617.
SPECIALE C, OKUNO E, SCHWARCZ R: Increased quinolinic acid metabolism following neuronal degeneration in the rat hippocampus. Brain Res 1987; 436: 18-24. SPYDERVOLD OS, ZAHEER-BAQUER N, McLEAN P, et al.: The effect of quinolinic acid on the content and distribution of hepatic metabolites. Arch Biochem Biophys 1974; 164: 590-601. SWAIN JL, HOLMES EW: Nucleotide metabolism in cardiac muscle. In: FOZZARD HV et al. (Eds.): The heart and cardiovasculat system. Raven Press New York 1986 pp. 911-929. TOBES MC, MASON M: L-Kynurenine aminotransferase and L-alpha-aminoadipate aminotransferase. Evidence for identity. Biochem Biophys Res Commun 1975; 62: 390-397. VENEZIALE CM, WALTER P, KNEER N, et al.: Influnce of 1tryptophan and its metabolites on gluconeogenesis in the isolated, perfused liver. Biochem 1967; 6: 2129-2138. WILLIAMS RT: Chemistry of detoxication. In: Drugs and the liver. Arzneimittel und Leber. III Int. Symp. 12.-14. Oktober 1973, Freiburg i. Br. Schattauer Verlag StuttgartN.York 1975 pp. 51-64. WOLF H: Studies of tryptophan metabolism in man. Scand J Clin Lab Invest 1974; suppl. 136; 33: 13-34. WOLFENSBERGER A, AMSLER H, CUENOD M, et al.: Identification of quinolinic acid in rat and human brain tissue. Neurosci Lett 1983; 41: 247-254.
Exp Toxic Pathol47 (1995) 5
379