Aminotransferases induction

Y. N. Sun, D. C. DuBois, R. R. Ahnon, N. A. Pyszczynski, and W. J. Jusko, Dose-dependence and repeated-dose studies for receptor/gene-mediated pharmacodynamics of methylprednisolone on glucocorticoid receptor down-regulation and tyrosine aminotransferase induction in rat liver. J Pharmacokinet Biopharm 26 619-648 (1998). 

Baxter, J., and G. M. Tomkins. 1970. The relationship between glucocorticoid binding and tyrosine aminotransferase induction in hepatoma tissue culture cells. Proc. Nat. Acad. Sci. U.S.A., 65 709. 

K6. Keller, N., Richardson, U. I., and Yates, F. E., Protein binding and the biological activity of corticosteroids in vivo induction of hepatic and pancreatic alanine aminotransferases by corticosteroids in normal and estrogen-treated rats. Endocrinology 84, 49-62 (1969). 

Typical side effects are constitutional in nature, including a flu-like syndrome within 6 hours after dosing in more than 30% of patients that tends to resolve upon continued administration. Other potential adverse effects include thrombocytopenia, granulocytopenia, elevation in serum aminotransferase levels, induction of autoantibodies, nausea, fatigue, headache, arthralgias, rash, alopecia, anorexia, hypotension, and edema. Severe neuropsychiatric side effects may occur. Absolute contraindications to therapy are psychosis, severe depression, neutropenia, thrombocytopenia, symptomatic heart disease, decompensated cirrhosis, uncontrolled seizures, and a history of organ transplantation (other than liver). Alfa interferons are abortifacient in primates and should not be administered in pregnancy. 

It has been noted in the case of several enzymes that their artificial prococious induction is reversible in that, unless the injection of the appropriate hormone is repeated, the enzyme disappears again. Why is it then that after its natural appearance at the scheduled time, the persistence of the enzyme does not hinge on the continued action of that hormone For example, glucocorticoid is undoubtedly the essential developmental stimulus for the hepatic ornithine aminotransferase(14), a member of the late suckling cluster. Its normal emergence on day 12 can be prevented by prior adrenalectomy, its precocious synthesis (5-10 days before schedule) can be evoked by an injection of cortisol, and yet no loss at all is incurred by adrenalectomy performed at or after the time at which ornithine aminotransferase has attained near adult or adult values (i.e. on day 20 or later). 

GH has been shown to induce a number of enzymes concerned with amino acid metabolism in the liver of the hypophysectomized rat (in vivo or in perfused liver [78]). Induced enzymes include tyrosine aminotransferase, tryptophan oxygenase and ornithine decarboxylase. The effects are complex, particularly in relation to interaction with glucocorticoids, and in some experiments GH lowered enzyme levels induced by glucocorticoids, although given alone it led to induction of these enzymes. 

Figure 5.4. Schematic representation of the hybrid QSPR-PD model for corticosteroid action on tyrosine aminotransferase (TAT) induction in rat hepatocytes. In this model, the free intracellular concentration is a constant fraction (a) of the plasma concentration, Bmax is the total amount of glucocorticoid receptor (GR), and Kq is an equilibrium dissociation constant.17...

Dundjerski, J., B. Butorovic, J. Kipic, D. Trajkovic and G. Matic. Cadmium affects the activity of rat liver tyrosine aminotransferase and its induction by dexamethasonc. Arch. Toxicol. 70 390-395, 1996. 

The induction of hepatic tyrosine aminotransferase (TAT) mRNA and activity is a classical measure of corticosteroid-mediated pharmacogenomic effects. The TAT dynamics are modeled in a manner consistent with precursor-dependent models, where the stimulation function acts on the production rate of the precursor species ... 

Deguchi, T. and Barchas, J., Induction of hepatic tyrosine aminotransferase by indole amines, /. Biol. Chem., 246[23], 7217, 1971. 

Kato, K., Selective repression of benzoate or tryptophan mediated induction of liver tyrosine aminotransferase by phentolamine in adrenalectomized rats, FEBS Lett., 8, 316, 1970. 

Pamart, B., Girard-Globa, A., and Bourdel, G., Induction of tyrosine aminotransferase and depression of protein synthesis in rat liver by a tryptophan-free mixture of amino acids,. Nutr., 104[9], 1149, 1974. 

Metabolism of carbohydrates, lipids and proteins, anti-inflammatory, iimmunsuppressive induction of Tyr-aminotransferase and of T rp-cyclooxygenase... 

Fig. 25.7. The development of alcohol-induced hepatitis. (1) Acetaldehyde adduct formation decreases protein synthesis and impairs protein secretion. (2) Free radical injury results partly from acetaldehyde adduct formation with glutathione. (3) Induction of MEOS increases formation of free radicals, which leads to Upid peroxidation and cell damage. (4) Mitochondrial damage inhibits the electron transport chain, which decreases acetaldehyde oxidation. (5) Microtubule damage increases VLDL and protein accumulation. (6) CeU damage leads to release of the hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

Fig. 2. Induction of tyrosine aminotransferase in HTC cells by dexamethasone phosphate. A culture of HTC cells, grown to a density of about 8x10 cells/ml, was resuspended in fresh medium and divided into two portions. To the first portion, dexamethasone phosphate was added to a final concentration of 5 X 10-5 M. The other portion was used as a control. Enzyme activity was assayed as described in Martin et al., 1969a, and is expressed as milliunits of enzyme per milligram of cell protein. (From Tomkins et al. Science, 166 1474.)...

Gelehrter, T. D., and G. M. Tomkins. 1967. The role of RNA in the hormonal induction of tyrosine aminotransferase in mammalian cells in tissue culture. J. Molec. Biol., 29 59. 

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