Clinical significance of plasma c-GMP levels in various hepatobiliary disorders

Plasma guanosine 3', 5'-monophosphate (cyclic GMP) were measured by radioimmunoassay in 100 patients with various liver diseases, 24 normal subjects, 16 patients with various types of neoplastic disease and 3 patients with uremia. In patients with acute hepatitis, fatty liver, obstructive...

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Published inKanzo Vol. 22; no. 5; pp. 626 - 636
Main Authors KANO, Takashi, KAWAI, Hideko, KOJIMA, Takao, Muro, Yasutoshi, TAKAHASHI, Yoshiyata
Format Journal Article
LanguageEnglish
Japanese
Published The Japan Society of Hepatology 25.05.1981
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Abstract Plasma guanosine 3', 5'-monophosphate (cyclic GMP) were measured by radioimmunoassay in 100 patients with various liver diseases, 24 normal subjects, 16 patients with various types of neoplastic disease and 3 patients with uremia. In patients with acute hepatitis, fatty liver, obstructive jaundice and intrahepatic cholestasis plasma c-GMP levels did not differ significantly from those in normal subjects. In contrast plasma c-GMP were significantly elevated in patients with chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, fulminant hepatitis, various types of neoplastic disease and uremia. The degree of elevation averaged threefold in patients with liver cirrhosis, fourfold in hepatocellular carcinoma and liver cirrhosis with hepatic encephalopathy and sixfold in fulminant hepatitis. In addition significant correlations between plasma c-GMP levels and liver function test (i.e., hepaplastin test, albumin and choline esterase) were observed. Furthermore the measurement of plasma c-GMP levels was useful for the early diagnosis and efficacy of various therapies in patients with hepatocellular carcinoma and fulminant hepatitis. These results suggest that determination of plasma c-GMP is of practical importance for evaluation of severity of hepatocellular damage and malignant transformation and for estimation of hepatic encephalopathy. The mechanism of increased plasma c-GMP content in patients with liver diseases in not clear, although both increased rate of c-GMP production in liver and/or brain tissues and diminished hepatic uptake of c-GMP could be involved.
AbstractList Plasma guanosine 3', 5'-monophosphate (cyclic GMP) were measured by radioimmunoassay in 100 patients with various liver diseases, 24 normal subjects, 16 patients with various types of neoplastic disease and 3 patients with uremia. In patients with acute hepatitis, fatty liver, obstructive jaundice and intrahepatic cholestasis plasma c-GMP levels did not differ significantly from those in normal subjects. In contrast plasma c-GMP were significantly elevated in patients with chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, fulminant hepatitis, various types of neoplastic disease and uremia. The degree of elevation averaged threefold in patients with liver cirrhosis, fourfold in hepatocellular carcinoma and liver cirrhosis with hepatic encephalopathy and sixfold in fulminant hepatitis. In addition significant correlations between plasma c-GMP levels and liver function test (i.e., hepaplastin test, albumin and choline esterase) were observed. Furthermore the measurement of plasma c-GMP levels was useful for the early diagnosis and efficacy of various therapies in patients with hepatocellular carcinoma and fulminant hepatitis. These results suggest that determination of plasma c-GMP is of practical importance for evaluation of severity of hepatocellular damage and malignant transformation and for estimation of hepatic encephalopathy. The mechanism of increased plasma c-GMP content in patients with liver diseases in not clear, although both increased rate of c-GMP production in liver and/or brain tissues and diminished hepatic uptake of c-GMP could be involved.
Author Muro, Yasutoshi
KANO, Takashi
KAWAI, Hideko
TAKAHASHI, Yoshiyata
KOJIMA, Takao
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  fullname: TAKAHASHI, Yoshiyata
  organization: The First Department of Internal Medicine, Gifu University Medical School
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References 28) Koide, Y. et al.: Alterations in the intracellular distribution of c-GMP and guanylate cyclase activity during rat liver regeneration. J. Biol. Chem., 253: 4439, 1978.
9) Goldberg, N.D. et al.: Biologic regulation through opposing influences of cyclic GMP and cyclic AMP: the Yin-Yan hypothesis. Advances in Cyclic Nucleotide Research, 5: 307, 1975.
34) Breese, G.R. et al.: Effects of dopaminergic agonist and antagonists of cerebellar guanosine 3', 5'-monophosphate (c-GMP). Life Sciences, 23: 533, 1978.
1) Ashman, D.F. et al.: Isolation of adenosine 3', 5'-monophosphate and guanosine 3', 5'-monophosphate from rat urine. Biochem. Biophys. Res. Commun., 11: 330, 1963.
32) Ferrendelli. J.A. et al.: Regulation of levels of guanosine cyclic 3', 5'-monophosphate in the control nervous system: Effects of depolarizing agents. Mol. Pharmacol., 9: 445, 1973.
2) Murad, F. et al.: A simple, sensitive proteinbinding assay for guanosine 3', 5'-monophosphate. Proc. Natl. Acad. Sci. USA, 68: 736, 1971.
24) Hadden, J.W. et al.: Cyclic GMP in cholinergic and mitogenic modulation of lymphocyte metabolism and proliferation. Federation Proc., 32: 1022, 1973.
3) Steiner, A.L. et al.: Radioimmunoassay for cyclic nucleotides I. Preparation of antibodies and iodinated cyclic nucleotides. J. Biol. Chem., 247: 1106, 1972.
6) Illiano, G. et al.: Guanosine 3', 5'-cyclic monophosphate and the action of insulin and acetyl choline. Proc. Natl. Acad. Sci. USA, 70: 2443, 1973.
20) Neethling, A.C. et al.: Cyclic GMP excretion and hepatoma. Lancet, 11: 579, 1976.
23) Kuehl, F.A. et al.: Estrogen-related increases in uterine guanosine 3': 5'-cyclic monophosphate levels. Proc. Natl. Acad. Sci. US, 71: 1866, 1974.
18) Wood, P.J. et al.: Plasma and urine cyclic nucleotide levels in malignant disease and cirrhosis of liver. J. Clin. Pathol., 32: 998, 1979.
22) 前久保博士他:肝硬変症における血漿cyclicGMP濃度.肝臓,21: 901, 1980.
30) Kuo, J.F. et al.: Cyclic nucleotide-dependent protein kinases. X. An assay method for the measurement of guanosine 3', 5'-monophosphate in various biological materials and a study of agents regulating its levels in heart and brain. J. Biol. Chem., 247: 16, 1972.
13) Honma, M. et al.: An ultrasensitive method for the simultaneous determination of cyclic AMP and cyclic GMP in small-volume samples from blood and tissue. Biochem. Med., 18: 257, 1979.
36) Fischer, J.E. et al.: Pathogenesis and therapy of hepatic coma. In: Progress in liver disease Vol. V. edited by Popper, H. Grune & Stratton Inc. N.Y. p. 363, 1976.
39) Steiner, A.L. et al.: Radioimmunoassay for cyclic nucleotides. III. Effect of ischemia changes during development and regional distribution of adenosine 3', 5'-monophosphate and guanosine 3', 5'-monophosphate in mouse brain. J. Biol. Chem., 247, 1121, 1972.
37) Schenker, S. et al.: Studies on the intracerebral toxicity of ammonia. J. Clin. Invest., 46: 838, 1967.
31) Ferrendelli, J.A. et al.: Elevation of cyclic GMP levels in central nervous system by excitatory and inhibitory amino acids. J. Neurochem., 22: 535, 1974.
29) Exton, J.H. et al.: Effects of guanosine 3', 5'-monophosphate on the perfused rat liver. J. Biol. Chem., 246: 2658, 1971.
33) Ferrendelli, J.A. et al.: Effects of amphetamine, chlorpromazine and reserpine on cyclic GMP and cyclic AMP levels in mouse cerebellum. Biochem. Biophys. Res. Commun., 46: 2114, 1972.
7) DeAsua, L.J. et al.: Initiation of cell proliferation in cultured mouse fibroblasts by prostaglandin F2α. Proc. Natl. Acad. Sci. USA, 72: 2724, 1975.
8) Hadden, J.W. et al.: Guanosine 3', 5'-cyclic monophosphate: a possible intracellular mediator of mitogenic influences in lymphocytes. Proc. Natl. Acad. Sci. US, 69: 3024, 1972.
19) Goldberg, M.L. et al.: Cyclic AMP and cyclic GMP content and binding in malignancy. Biochem. Biophys. Res. Commun., 62: 320, 1975.
27) Short, J. et al.: Cyclic adenosine 3', 5'-monophosphate and the induction of deoxyribonucleic acid synthesis in liver. J. Biol. Chem., 250: 3602, 1975.
26) MacManus, J.P. et al.: Increases in rat liver cyclic AMP concentrations prior to initiation of DNA synthesis following partial hepatectomy or hormone infusion. Biochem. Biophys. Res. Commun., 49: 1201, 1972.
17) Mikuni, M. et al.: Circadian variations in plasma 3': 5'-cyclic adenosine monophosphate and 3': 5'-cyclic guanosine monophosphate of normal adults. Life Sciences, 22: 667, 1978.
38) Grain, U.B. et al.: Cerebral edema in the rat with galactosamine induced severe hepatitis. Experientia, 34: 1501, 1978.
21) Chawla, R.K. et al.: Plasma and urine cyclic guanosine 3': 5'-monophosphate in disseminated cancer. Ann. Int. Med., 91: 862, 1979.
15) Craven, P.A. et al.: Inhibition by retinol and butylated hydroxyanisole of carcinogen-mediated increases in guanylate cyclase activity and guanosine 3', 5'-monophosphate accumulation. Cancer Res., 37: 4088, 1977.
4) Steiner, A.L. et al.: Radioimmunoassay for cyclic nucleotides II. Adenosine 3', 5'-monophosphate and guanosine 3', 5'-monophosphate in mammalian tissues and body fluids. J. Biol. Chem., 247: 1114, 1972.
16) DeRubertis, F.R. et al.: Stimulation of soluble guanylate cyclase activity and cellular accumulation of cyclic guanosine 3', 5'-monophosphate by the carcinogen 4-nitroquinoline 1-oxide: brief communication. J. Natl. Cancer Inst., 59: 1741, 1977.
10) Thomas, E.W. et al.: Adenosine 3', 5'-monophosphate and guanosine 3', 5'-monophosphate: concentrations in Morris hepatomas of different growth rates. Biochim. Biophys. Acta. 297: 564, 1973.
14) Roll, T.W. et al.: Formation of a cyclic adenine ribonucleotide by tissue particles. J. Biol. Chem., 232: 1065, 1958.
35) Stefano, G.B. et al.: Methionine enkephalin and morphine alter monoamine and cyclic nucleotide levels in the cerebral ganglia of the fresh water bivalve anodonta cygnea. Life Sciences, 25: 291, 1979.
40) Price, T.D. et al.: Organophosphates of urine, including adenosine 3', 5'-monophosphate and guanosine 3', 5'-monophosphate. Biochim. Biophys. Acta, 138: 452, 1967.
11) DeRubertis, F.R. et al.: Increased guanylate cyclase activity and guanosine 3', 5'-mono. phosphate content in ethionine-induced hepatomas. Cancer Res., 37: 15, 1977.
5) George, W.J. et al.: Elevations of guanosine 3', 5'-cyclic phosphate in rat heart after perfusion with acetyl choline. Proc. Natl. Acad. Sci. USA, 66: 398, 1970.
25) Seifert, W.E. et al.: Possible involvement of cyclic GMP in growth control of cultured mouse cells. Nature, 248: 138, 1974.
12) Ferrendelli, J.A.: Role of cyclic GMP in the function of the central nervous system. In: Cyclic nucleotides in disease edited by Weiss, B. University Park Press, Baltimore, Maryland, USA, p. 377, 1974.
References_xml – reference: 9) Goldberg, N.D. et al.: Biologic regulation through opposing influences of cyclic GMP and cyclic AMP: the Yin-Yan hypothesis. Advances in Cyclic Nucleotide Research, 5: 307, 1975.
– reference: 13) Honma, M. et al.: An ultrasensitive method for the simultaneous determination of cyclic AMP and cyclic GMP in small-volume samples from blood and tissue. Biochem. Med., 18: 257, 1979.
– reference: 24) Hadden, J.W. et al.: Cyclic GMP in cholinergic and mitogenic modulation of lymphocyte metabolism and proliferation. Federation Proc., 32: 1022, 1973.
– reference: 35) Stefano, G.B. et al.: Methionine enkephalin and morphine alter monoamine and cyclic nucleotide levels in the cerebral ganglia of the fresh water bivalve anodonta cygnea. Life Sciences, 25: 291, 1979.
– reference: 32) Ferrendelli. J.A. et al.: Regulation of levels of guanosine cyclic 3', 5'-monophosphate in the control nervous system: Effects of depolarizing agents. Mol. Pharmacol., 9: 445, 1973.
– reference: 34) Breese, G.R. et al.: Effects of dopaminergic agonist and antagonists of cerebellar guanosine 3', 5'-monophosphate (c-GMP). Life Sciences, 23: 533, 1978.
– reference: 40) Price, T.D. et al.: Organophosphates of urine, including adenosine 3', 5'-monophosphate and guanosine 3', 5'-monophosphate. Biochim. Biophys. Acta, 138: 452, 1967.
– reference: 2) Murad, F. et al.: A simple, sensitive proteinbinding assay for guanosine 3', 5'-monophosphate. Proc. Natl. Acad. Sci. USA, 68: 736, 1971.
– reference: 37) Schenker, S. et al.: Studies on the intracerebral toxicity of ammonia. J. Clin. Invest., 46: 838, 1967.
– reference: 33) Ferrendelli, J.A. et al.: Effects of amphetamine, chlorpromazine and reserpine on cyclic GMP and cyclic AMP levels in mouse cerebellum. Biochem. Biophys. Res. Commun., 46: 2114, 1972.
– reference: 31) Ferrendelli, J.A. et al.: Elevation of cyclic GMP levels in central nervous system by excitatory and inhibitory amino acids. J. Neurochem., 22: 535, 1974.
– reference: 27) Short, J. et al.: Cyclic adenosine 3', 5'-monophosphate and the induction of deoxyribonucleic acid synthesis in liver. J. Biol. Chem., 250: 3602, 1975.
– reference: 28) Koide, Y. et al.: Alterations in the intracellular distribution of c-GMP and guanylate cyclase activity during rat liver regeneration. J. Biol. Chem., 253: 4439, 1978.
– reference: 7) DeAsua, L.J. et al.: Initiation of cell proliferation in cultured mouse fibroblasts by prostaglandin F2α. Proc. Natl. Acad. Sci. USA, 72: 2724, 1975.
– reference: 21) Chawla, R.K. et al.: Plasma and urine cyclic guanosine 3': 5'-monophosphate in disseminated cancer. Ann. Int. Med., 91: 862, 1979.
– reference: 5) George, W.J. et al.: Elevations of guanosine 3', 5'-cyclic phosphate in rat heart after perfusion with acetyl choline. Proc. Natl. Acad. Sci. USA, 66: 398, 1970.
– reference: 18) Wood, P.J. et al.: Plasma and urine cyclic nucleotide levels in malignant disease and cirrhosis of liver. J. Clin. Pathol., 32: 998, 1979.
– reference: 23) Kuehl, F.A. et al.: Estrogen-related increases in uterine guanosine 3': 5'-cyclic monophosphate levels. Proc. Natl. Acad. Sci. US, 71: 1866, 1974.
– reference: 3) Steiner, A.L. et al.: Radioimmunoassay for cyclic nucleotides I. Preparation of antibodies and iodinated cyclic nucleotides. J. Biol. Chem., 247: 1106, 1972.
– reference: 12) Ferrendelli, J.A.: Role of cyclic GMP in the function of the central nervous system. In: Cyclic nucleotides in disease edited by Weiss, B. University Park Press, Baltimore, Maryland, USA, p. 377, 1974.
– reference: 1) Ashman, D.F. et al.: Isolation of adenosine 3', 5'-monophosphate and guanosine 3', 5'-monophosphate from rat urine. Biochem. Biophys. Res. Commun., 11: 330, 1963.
– reference: 4) Steiner, A.L. et al.: Radioimmunoassay for cyclic nucleotides II. Adenosine 3', 5'-monophosphate and guanosine 3', 5'-monophosphate in mammalian tissues and body fluids. J. Biol. Chem., 247: 1114, 1972.
– reference: 11) DeRubertis, F.R. et al.: Increased guanylate cyclase activity and guanosine 3', 5'-mono. phosphate content in ethionine-induced hepatomas. Cancer Res., 37: 15, 1977.
– reference: 22) 前久保博士他:肝硬変症における血漿cyclicGMP濃度.肝臓,21: 901, 1980.
– reference: 19) Goldberg, M.L. et al.: Cyclic AMP and cyclic GMP content and binding in malignancy. Biochem. Biophys. Res. Commun., 62: 320, 1975.
– reference: 30) Kuo, J.F. et al.: Cyclic nucleotide-dependent protein kinases. X. An assay method for the measurement of guanosine 3', 5'-monophosphate in various biological materials and a study of agents regulating its levels in heart and brain. J. Biol. Chem., 247: 16, 1972.
– reference: 39) Steiner, A.L. et al.: Radioimmunoassay for cyclic nucleotides. III. Effect of ischemia changes during development and regional distribution of adenosine 3', 5'-monophosphate and guanosine 3', 5'-monophosphate in mouse brain. J. Biol. Chem., 247, 1121, 1972.
– reference: 38) Grain, U.B. et al.: Cerebral edema in the rat with galactosamine induced severe hepatitis. Experientia, 34: 1501, 1978.
– reference: 8) Hadden, J.W. et al.: Guanosine 3', 5'-cyclic monophosphate: a possible intracellular mediator of mitogenic influences in lymphocytes. Proc. Natl. Acad. Sci. US, 69: 3024, 1972.
– reference: 6) Illiano, G. et al.: Guanosine 3', 5'-cyclic monophosphate and the action of insulin and acetyl choline. Proc. Natl. Acad. Sci. USA, 70: 2443, 1973.
– reference: 10) Thomas, E.W. et al.: Adenosine 3', 5'-monophosphate and guanosine 3', 5'-monophosphate: concentrations in Morris hepatomas of different growth rates. Biochim. Biophys. Acta. 297: 564, 1973.
– reference: 20) Neethling, A.C. et al.: Cyclic GMP excretion and hepatoma. Lancet, 11: 579, 1976.
– reference: 29) Exton, J.H. et al.: Effects of guanosine 3', 5'-monophosphate on the perfused rat liver. J. Biol. Chem., 246: 2658, 1971.
– reference: 14) Roll, T.W. et al.: Formation of a cyclic adenine ribonucleotide by tissue particles. J. Biol. Chem., 232: 1065, 1958.
– reference: 16) DeRubertis, F.R. et al.: Stimulation of soluble guanylate cyclase activity and cellular accumulation of cyclic guanosine 3', 5'-monophosphate by the carcinogen 4-nitroquinoline 1-oxide: brief communication. J. Natl. Cancer Inst., 59: 1741, 1977.
– reference: 36) Fischer, J.E. et al.: Pathogenesis and therapy of hepatic coma. In: Progress in liver disease Vol. V. edited by Popper, H. Grune & Stratton Inc. N.Y. p. 363, 1976.
– reference: 17) Mikuni, M. et al.: Circadian variations in plasma 3': 5'-cyclic adenosine monophosphate and 3': 5'-cyclic guanosine monophosphate of normal adults. Life Sciences, 22: 667, 1978.
– reference: 25) Seifert, W.E. et al.: Possible involvement of cyclic GMP in growth control of cultured mouse cells. Nature, 248: 138, 1974.
– reference: 26) MacManus, J.P. et al.: Increases in rat liver cyclic AMP concentrations prior to initiation of DNA synthesis following partial hepatectomy or hormone infusion. Biochem. Biophys. Res. Commun., 49: 1201, 1972.
– reference: 15) Craven, P.A. et al.: Inhibition by retinol and butylated hydroxyanisole of carcinogen-mediated increases in guanylate cyclase activity and guanosine 3', 5'-monophosphate accumulation. Cancer Res., 37: 4088, 1977.
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Title Clinical significance of plasma c-GMP levels in various hepatobiliary disorders
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