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Dose-response relationship and low dose extrapolation in chemical carcinogenesis [commentary]
(1990)
Data supporting various dose-respome relationships in chemical carcinogenesis are summarized. General principles are derived to explain the relationships between exposure dose, JI>NA adduct Ievel, induction of genetic changes, and tumor incidence. Some mechanistic aspects of epigenetic carcinogens (stimulation of ceU division and maldlfl'erentlation) are analyzed in a similar way. In a bomogeneous pnpulation, non-linearities are frequent. They are due to pbenomena of induction or saturation of enzymatic activities and to the multi-step nature of carcinog~: if a carcinogen acce1erates more than one step, the SUperposition of the dose- response curves for the indJvidual steps can result in an exponential relationship. A fourth power of the dose was the maximum seen in animals (fonnaldehyde). At the lowest dose Ievels, a proportionality between dose and tumor induction is postulated independent of the mechanism of action if the carcinogen aceeierotes the endogenous proass responsible for spootaneous tumor formation. Low-dose thresholds are expected only for situations where the carcinogen acts in a way that has no endogenous counterpart. Epidemiologfcal studies in humans show linear dose- response curves in all but two investigations. The difference from the strongly nonlinear slopes ·seen in animal studies could be due to the heterogeneity of the human population: if the individual sensitivity to a carcinogen is governed by a large number of genetic and Iife-style factors, the non-linea.rities will tend to cancel each other out and the dose- response curve becomes 'quasi-linear'.
Linear dose-response relationship for DNA adducts in rat liver from chronic exposure to aflatoxin B1
(1990)
Male F-344 rats were given eH]aßatoxin B1 (AFB1) in the drinking water at three exposure Ievels (0.02, 0.6, 20 J,Lgll, resulting in average dose Ievels of 2.2, 73, 2110 nglkg per day). After 4, 6 and 8 weeks, DNA was ~ted frorn the livers and analyzed for aßatoxin-DNA adducts. Tbe Ievel of DNA adducts did not increase significantly after 4 weeks, indicating that a steady-state for adduct formation and removal had nearly been reached. At 8 weeks, the adduct Ievels were 0.91, 32 and 850 nucleotide-aßatoxin adducts per to' nucleotides, i.e. clearly proportional to the dose. At the high dose Ievel, a near SO% tumor incidence would be expected in a 2-year bioassay with F -344 rats while the low dose used is within the range of estlmated human dietary exposures to aßatoxin in W estem countries. The proportionality seen between exposure and steady-state DNA adduct Ievel is discussed with respect to a linear extrapolation of the tumor risk to low dose.
Active neuropeptide Y receptors were solubilized from rabbit kidney membranes using the zwitterionic detergent 3-[ (3-cholamidopropy l)dimethylammonio ]- 1-propanesulfonic acid (CHAPS). In membrane fragmentsandsoluble extracts neuropeptide Y bindingwas time dependent, saturable, reversible, and of high affinity. Scatchard analysis of equilibrium binding data indicated a single class of binding sites with respective Kn and Bmax values of 0.09 nM and 530 fmol/mg of protein for the membrane-bound receptors and 0.10 nM and 1585 fmol/mg of protein for the soluble receptors. Neuropeptide Y bindingwas specifically inhibited by the nonhydrolyzable GTP analog guanosine 5' -0- (3-thiotripbosphate) in a concentration-dependent manner, with IC\(_{50}\) values of 28 and 0.14 \(\mu\)M for membrane- bound and soluble receptors, respectively, suggesting that neuropeptide Y receptors are functionally coupled to GTP-binding regulatory proteins. CrossHoking studies were performed with the heterobifunctional N-hydroxysuccinimidyl-4-azidobenzoate and the monofunctional neuropeptide Y derivative, azidobenzoyl and led to the identification of a 100 kDa peptide that should represent the covalently labeled neuropeptide Y receptor.
The effects of guanine nucleotides on binding of 8-cyclopentyl-1,3-[\(^3\)H]dipropylxanthine [\(^3\)H]DPCPX), a highly selective A\(_1\) adenosine receptor antagonist, have been investigated in rat brain membranes and solubilized A\(_1\) receptors. GTP, which induces uncoupling of receptors from guanine nucleotide binding proteins, increased binding of [\(^3\)H]DPCPX in a concentration-dependent manner. The rank order of potency for different guanine nucleotides for increasing [\(^3\)H]DPCPX bindingwas the same as for guanine nuc1eotide-induced inhibition of agonist binding. Therefore, a role for a guanine nucleotide binding protein, e.g., G\(_i\), in the regulation of antagonist binding is suggested. This was confirmed by inactivation ofGi by N-ethylmaleimide (NEM) treatment of membranes, which resulted in an increase in [\(^3\)H]DPCPX binding similar to that seen with addition of GTP. Kinetic and equilibrium binding studies showed that the GTP- or NEM-induced increase in antagonist binding was not caused by an affinity change of A\(-1\) receptors for [\(^3\)H]DPCPX but by an increased Bmu value. Guanine nucleotides had similar effects on membrane-bound and solubilized receptors, with the effects in the solubilized system being more pronounced. In the absence of GTP, when rnost receptors are in a high-affinity state for agonists, only a few receptors are labeled by [\(^3\)H]DPCPX. It is suggested that [\(^3\)H]DPCPX binding is inhibited when receptors are coupled to G\(_i\). Therefore, uncoupling of A\(_1\) receptors from G\(_i\) by guanine nucleotides or by inactivation of G\(_i\) with NEM results in an increased antagonist binding.
Key Words: Adenosine receptors-8 -Cyclopentyl-1,3-eH]dipropylxanthine-Antagenist binding-Guanine nucleotide effects. Klotz K.-N. et al. Guanine nucleotide etfects on 8-cyclopentyl-1 ,3-eH]dipropylxanthine binding to membrane-bound and solubilized A1 adenosine receptors of rat brain. J. Neurochem. 54, 1988-1994 (1990).