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The potential health risk posed by the endogenous formation of N-nitroso compounds (NOC) from nitrosation of dietary ureas, guanidines, amides, amino acids and amanes (primary, secondary and aromatic) was estimated according to the model:
Risk = ( daily intake of precursor] X (gastric concentration of nitrite ]n X [nitrosatability rate constant] X [cilrcinogenicity of derivative].
The daily intakes ofthese compound classes span five orders ofmagnitude (100 g/day amides, top; 1-10 mg/day secondary amines, ureas, bottom); the nitrosation rate constants span seven orders of magnitude (aryl amines, ureas, top; amides, secondary amines, bottom); and the carcinogenicity estimates span a 10 000-fold range from 'very strong' to 'virtually noncarcinogenic'. The resulting risk estimates likewise span an enormous range (nine orders of magnitude ): dietary ureas and aromatic amines combined with high nitrite concentration could pose as great a risk as the intake of preformed N-nitrosodimethylamine in the diet. In contrast, the risk posed by the in-vivo nitrosation of primary and secondary amines is probably negligible. The risk contributed by amides (including protein), guanidines and primary amino acids is intermediate between these two extremes.
The ligand-binding subunit ofthe A1 adenosine receptor has been identified in membranes with the photoaffinity Iabel R-2-azido-N6-p-hydroxyphenylisopropyladenosine (R-AHPIA). Covalent labelling ofthe A1 receptor can also be achieved in intact cells. The dissociation of the radioiodinated label (1251-AHPIA) from isolated rat fat cells was incomplete after UV irradiation, leaving about 20°/o of irreversible specific binding. Such covalent labelling of the receptor led to a concentration-dependent reduction of cellular cyclic AMP levels. This persistent effect of covalent labeHing occurred with an IC50 value of 9 nM, as compared to an IC50 value of 0.9 nM for the direct reduction of cyclic AMP Ievels by the ligand. The difference in the IC5o values can be explained by assuming spare receptors. This hypothesis was verified in binding studies using [ 3HJPIA as a radioligand. R-AHPIA inhibited binding of [3H)PIA to intact fat cells with a K1 value of about 20 nM, which is about 20 tim es high er than the corresponding IC50 value of cyclic AMP reduction. These data show that the A1 receptor is activated according to the occupancy theory. The high sensitivity of the activation in intact ceJis is due to a large number of spare receptors.
We have previously reported that in several renal cell types, adenosine receptor agonists inhibit adenylyl cyclase and activate phospholipase C via a pertussis toxin-sensitive G protein. In the present study, in 28A cells, both uf these adenosine receptor-mediated responses were inhibited by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). a highly selective A1 adenosine receptor antagonist. The binding characteristics of the adenosine A 1 receptor in the 28A renal cell line were studied using the radiolabeled antagonist f:1H]DPCPX to determine whether two separate binding sites could account for these responses. Saturation binding of [: 1H]DPCPX to 28A cell membranes revealed a single class of A1 binding sites with an apparent Kd value of 1.4 nM and maximal binding capacity of 64 fmol/mg protein. Competition experiments with a variety of adenosine agonists gave biphasic displacement curves with a pharmacological profile characteristic of A1 receptors. Comparison of [: 1H]DPCPX competition binding data from 28A cell membranes with rabbit brain membranes, a tissue with well-characterized A1 receptors, reveals that the A 1 receptor population in 28A cells has similar agonist binding affinities to the receptor population in brain but has a considerably lower density. Addition of guanosine ;)' -triphosphate ( 100 ,uM) to 28A cell membranes caused the competition curves to shift from biphasic to monophasic. indicating that the A1 receptors exist in two interconvertible affinity states because of their coupling to G proteins. In the absence of evidence for subpopulations of the A1 receptor, it appears that in 28A cells. A single A1 receptor population. As defined by ligand binding characteristics, couples via one or more pertussis toxin-sensitive guanine nucleotide binding proteins to two different biological signaling mechanisms.
It has previously been shown that covalent incorporation of the photoreactive adenosine derivative (R)-2-azido-N6-p-hydroxyphenytisopropyladenosine [(R)-AHPIA] into the A, adenosine receptor of intact fat cells leads to a persistent activation of this receptor, resulting in a reduction of celular cAMP Ieveis [Mol. Pharmacol. 30:403-409 (1986)]. In contrast, covalent incorporation of (R)-AHPIA into human platelet membranes, which contain only stimulatory A2 adenosine receptors, reduces adenytate cyclase Stimulation via these receptors. This effect of (R)-AHPIA is specific for the A2 receptor and can be prevented by the adenosine receptor antagonist theophylline. Binding studies in-dicate that up to 90% of A2 receptors can be blocked by photoincorporation of (R)-AHPIA. However, the remaining 10-20% of A2 receptors are sufficient to mediate an adenylate cyclase Stimulation of up to SOOk of the control value. Similarly, the activation via these 10-20% of receptors occurs with a halflife that is only 2 times Ionger than that in control membranes. This indicates the presence of a receptor reserve, with respect to both the extent and the rate of adenytate cyclase Stimulation. These observations require a modification of the models of receptor-adenytate cyclase coupling, which is described in the accompanying paper [Mol. Pharmacol. 39:524-530 (1991)].