Catecholamine accumulation

The amino acid tyrosine is the starting point in the synthesis of the catecholamines and of the thyroid hormones tetraiodothyronine (thyroxine T4) and triiodothyronine (T3) (Figure 42-2). T3 and T4 are unique in that they require the addition of iodine (as T) for bioactivity. Because dietary iodine is very scarce in many parts of the world, an intricate mechanism for accumulating and retaining T has evolved. 

The turnover rate of a transmitter can be calculated from measurement of either the rate at which it is synthesised or the rate at which it is lost from the endogenous store. Transmitter synthesis can be monitored by administering [ H]- or [ " C]-labelled precursors in vivo these are eventually taken up by neurons and converted into radiolabelled product (the transmitter). The rate of accumulation of the radiolabelled transmitter can be used to estimate its synthesis rate. Obviously, the choice of precursor is determined by the rate-limiting step in the synthetic pathway for instance, when measuring catecholamine turnover, tyrosine must be used instead of /-DOPA which bypasses the rate-limiting enzyme, tyrosine hydroxylase. 

Eldefrawi, A.T. and Eldefrawi, M.E. Phencyclidine interactions with the ionic channel of the acetylcholine receptor and elec-trogenic membrane. Proc Natl Acad Sci USA 77 1224-1228, 1980. Ary, T.C. and Komiskey, H.L. Basis of phencyclidine s ability to decrease the synaptosomal accumulation of 3H-catecholamines. 

The action of catecholamines released at the synapse is modulated by diffusion and reuptake into presynaptic nerve terminals. Catecholamines diffuse from the site of release, interact with receptors and are transported back into the nerve terminal. Some of the catecholamine molecules may be catabolized by MAO and COMT. The cate-cholamine-reuptake process was originally described by Axelrod [18]. He observed that, when radioactive norepinephrine was injected intravenously, it accumulated in tissues in direct proportion to the density of the sympathetic innervation in the tissue. The amine taken up into the tissues was protected from catabolic degradation, and studies of the subcellular distribution of catecholamines showed that they were localized to synaptic vesicles. Ablation of the sympathetic input to organs abolished the ability of vesicles to accumulate and store radioactive norepinephrine. Subsequent studies demonstrated that this Na+- and Cl -dependent uptake process is a characteristic feature of catecholamine-containing neurons in both the periphery and the brain (Table 12-2). 

In all tested organisms, PCBs — especially PCBs with 2,3,7,8-TCDD-like activity — adversely affected patterns of survival, reproduction, growth, metabolism, and accumulation. Common manifestations of PCB exposure in animals include hepatotoxicity (hepatomegaly, necrosis), immunotox-icity (atrophy of lymphoid tissues, suppressed antibody responses), neurotoxicity (impaired behavior and development, catecholamine alterations), increased abortion, low birth weight, embryolethality, teratogenicity, gastrointestinal ulceration and necrosis, bronchitis, dermal toxicity (chloracne, edema,... 

Urine catecholamines may also serve as biomarkers of disulfoton exposure. No human data are available to support this, but limited animal data provide some evidence of this. Disulfoton exposure caused a 173% and 313% increase in urinary noradrenaline and adrenaline levels in female rats, respectively, within 72 hours of exposure (Brzezinski 1969). The major metabolite of catecholamine metabolism, HMMA, was also detected in the urine from rats given acute doses of disulfoton (Wysocka-Paruszewska 1971). Because organophosphates other than disulfoton can cause an accumulation of acetylcholine at nerve synapses, these chemical compounds may also cause a release of catecholamines from the adrenals and the nervous system. In addition, increased blood and urine catecholamines can be associated with overstimulation of the adrenal medulla and/or the sympathetic neurons by excitement/stress or sympathomimetic drugs, and other chemical compounds such as reserpine, carbon tetrachloride, carbon disulfide, DDT, and monoamine oxidase inhibitors (MAO) inhibitors (Brzezinski 1969). For these reasons, a change in catecholamine levels is not a specific indicator of disulfoton exposure. 

Increased levels of urinary catecholamines may also be associated with accumulation of acetylcholine that resulted from acetylcholinesterase inhibition by disulfoton. No human data were located to support this, but limited animal data provide some evidence. Disulfoton exposure caused a 173% and 313% increase in urinary noradrenaline and adrenaline levels in rats, respectively, within 72 hours (Brzezinski 1969). The major metabolite of catecholamine metabolism, HMMA, was also detected in the urine from rats given acute doses of disulfoton (Wysocka-Paruszewska 1971). 

Although some steroids have been reported to reduce the toxic effects of some insecticides, the steroid ethylestrenol decreased the rate of recovery of depressed cholinesterase activity in disulfoton- pretreated rats (Robinson et al. 1978). The exact mechanism of this interaction was not determined. Ethylestrenol alone caused a small decrease in cholinesterase activity, and, therefore, resulted in an additive effect. Rats excreted less adrenaline and more noradrenaline when given simultaneous treatments of atropine and disulfoton compared with rats given disulfoton alone (Brzezinski 1973). The mechanism of action of disulfoton on catecholamine levels may depend on acetylcholine accumulation. In the presence of atropine, the acetylcholine effect on these receptors increases the ability of atropine to liberate catecholamines. 

Conjugation with glucuronyl residues is of great importance for the metabolic fate of bilirubin (S3), steroids (L5, M2, R8), catecholamines (W17) and other hydrophobic compounds (D8, D9). Neonatal accumulation of bilirubin in man and rats may trigger maturation of UDP-glucuronyltransferase (Bl, B2, T6). Delayed maturation of the enzyme, or its partial or total deficiency, are critical factors in the development of kernicterus (P6). Compared to other species partial deficiency of the... 

Ary, T.E., and Komiskey, H.L. Phencyclidine Inhibition of synaptosomal uptake and release of previously accumulated %-catecholamines. Pharmacologist 21 241, abst. no. 506, 1979. 

Hitzemann, R.J., Loh, H.H., and Domino, E.F. Effect of phencyclidine on the accumulation of C-catecholamines formed from C-tyro sine. Arch. Int. Pharmacodyn. Ther. 202 252-258, 1973. 

Biosynthesis of catecholamines. The rate-limiting step, conversion of tyrosine to dopa, can be inhibited by metyrosine (K-methyltyrosine). The alternative pathway shown by the dashed arrows has not been found to be of physiologic significance in humans. However, tyramine and octopamine may accumulate in patients treated with monoamine oxidase inhibitors. 

A considerable amount of evidence has accumulated recently for the transient existence of free-radical intermediates in systems containing oxidizing catecholamines. Walaas and Walaas and their co-workers have shown that the interaction of catecholamines with cupric ion (either bound, as in ceruloplasmin, or as the free ion, cf. ref. 80) results initially in reduction of the copper atom to the... 

Catecholamine neurotransmitters are subsequently inactivated by enzymic methylation of the 3-hydroxyl (via catechol-O-methyltransferase) or by oxidative removal of the amine group via monoamine oxidase. Monoamine oxidase inhibitors are sometimes used to treat depression, and these drugs cause an accumulation of amine neurotransmitters. Under such drug treatment, simple amines such as tyramine in cheese, beans, fish, and yeast extracts are also not metabolized and can cause dangerous potentiation of neurotransmitter activity. 

The role of cyclic AMP as modulator of prolactin secretion was first suggested by the finding of a stimulatory effect of cyclic AMP derivatives (17-22) and inhibitors of cyclic nucleotide phosphodiesterase activity such as theophylline and IBMX (22-26) on the secretion of this hormone. More convincing evidence supporting a role of cyclic AMP in the action of dopamine on prolactin secretion had to be obtained, however, by measurement of adenohypophysial adenylate cyclase activity or cyclic AMP accumulation under the influence of the catecholamine. As illustrated in Fig. 1, addition of 100 nM dopamine to male rat hemipituitaries led to a rapid inhibition of cyclic AMP accumulation, a maximal effect (30% inhibition) being already obtained 5 min after addition of the catecholamine. Thus, while dopamine is well known to stimulate adenylate cyclase activity in the striatum (27, 28), its effect at the adenohypophysial level in intact cells is inhibitory. Dopamine has also been found to exert parallel inhibitory effects on cyclic AMP levels and prolactin release in ovine adenohypophysial cells in culture (29) and purified rat mammotrophs (30). Using paired hemipituitaries obtained from female rats, Ray and Wallis (22) have found a rapid inhibitory effect of dopamine on cyclic AMP accumulation to approximately 75% of control. 

As Illustrated in Fig. 7, 3 yM CRF and 1 yM (-)Isoproterenol cause a 190 and 110% stimulation of adenylate cyclase activity In rat pars intermedia particulate fraction, respectively. An additive effect Is observed when both stimulatory agents are present. Dopamine (30 yM), on the other hand, has no significant effect alone. However, In the presence of GXP, the catecholamine causes a 40 to 60% Inhibition of adenylate cyclase activity stimulated by CRF, ISO or CRF + ISO. It can also be seen that while 0.3 mM GXP alone causes a 100% increase In basal adenylate cyclase activity, it leads to a marked potentiation of the effect of ISO and CRF on [ 2P] cyclic AMP accumulation. It should be noticed that In the absence of the guanyl nucleotide, dopamine has no Inhibitory effect on adenylate cyclase activity In any of the groups studied. 

The most well known of the naturally occurring phenethylamine derivatives (Table I) are the transmitters of the sympathetic nervous system, epinephrine, norepinephrine, and dopamine. All these compounds are 3,4-dioxygenated in the aromatic nucleus and are collectively known as the catecholamines. Norepinephrine is the transmitter of most sympathetic postganglionic fibers, dopamine is the predominant transmitter of the mammalian extrapyramidal system and of several mesocortical and mesolimbic neuronal pathways, and epinephrine is the major hormone of the adrenal medulla (363). The literature that has accumulated on the action of these compounds in higher animals is enormous. Metanephrine and normetanephrine are known from animals as deactivated metabolites of epinephrine and norepinephrine that result from the action of the enzyme catechol O-methyltransferase (364). 

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