The antiestrogenic drug tamoxifen forms DNA adducts in rat liver through two genotoxic metabolites, α-hydroxytamoxifen and α-hydroxy-N-desmethyltamoxifen. These have now each been resolved into R- ...and S-enantiomers. The work with α-hydroxytamoxifen was published earlier Osborne, et al. (2001) Chem. Res. Toxicol. 14, 888−893. Here, we publish results with α-hydroxy-N-desmethyltamoxifen. We prepared the derivative N-ethoxycarbonyl-N-desmethyltamoxifen-α-S-camphanate, separated it into two diastereoisomers, and hydrolyzed them to give (+)- and (−)-α-hydroxy-N-desmethyltamoxifen. The configuration of the (−)-isomer was shown to be S- by degradation of the above ester to a derivative of (−)-2-hydroxy-1-phenyl-1-propanone, which has already been shown to have S-configuration. The two enantiomers have the same chemical properties and were equally reactive toward DNA in vitro at pH 6. However, on treatment of rat hepatocytes in culture, R-(+)-α-hydroxy-N-desmethyltamoxifen gave 10 times as many DNA adducts as the S-(−)-isomer. This suggests that the R-isomer more readily undergoes sulfate conjugation to generate a reactive carbocation that attacks DNA.
Liver homogenates from rats fed tamoxifen (TAM) in the diet were shared among four different laboratories. TAM–DNA adducts were assayed by high pressure liquid chromatography–electrospray tandem mass ...spectrometry (HPLC–ES-MS/MS), TAM–DNA chemiluminescence immunoassay (TAM–DNA CIA), and 32P-postlabeling with either thin layer (32P-P–TLC) or liquid chromatography (32P-P–HPLC) separation. In the first study, rats were fed a diet containing 500 p.p.m. TAM for 2 months, and the values for measurements of the (E)-α-(deoxyguanosin-N2-yl)-tamoxifen (dG-N2-TAM) adduct in replicate rat livers varied by 3.5-fold when quantified using ‘in house’ TAM–DNA standards, or other approaches where appropriate. In the second study, rats were fed 0, 50, 250 or 500 p.p.m. TAM for 2 months, and TAM–DNA values were quantified using both ‘in house’ approaches as well as a newly synthesized N-methyl-3HTAM–DNA standard that was shared among all the participating groups. In the second study, the total TAM–DNA adduct values varied by 2-fold, while values for the dG-N2-TAM varied by 2.5-fold. Ratios of dG-N2-TAM:(E)-α-(deoxyguanosin-N2-yl)-N-desmethyltamoxifen (dG-N2-N-desmethyl-TAM) in the second study were ∼1:1 over the range of doses examined. The study demonstrated a remarkably good agreement for TAM–DNA adduct measurements among the diverse methods employed.
This paper studies the equilibria of a one-dimensional spatial model in which three candidates seek to maximize their probabilities of winning, are uncertain about the voters’ preferences, and may ...move whenever they wish. In the presence of enough uncertainty there is an equilibrium in which two candidates enter simultaneously at distinct positions in the first period and either the third candidate does not enter or enters between the first two in the second period.
The genotoxic tamoxifen metabolite α-hydroxytamoxifen has been resolved into R- and S-enantiomers. This was achieved by preparing its ester with S-camphanic acid, chromatographic separation into two ...diastereoisomers, and hydrolysis to give (+)- and (−)-α-hydroxytamoxifen. The configuration of the (−)-isomer was shown to be S- by degradation of an ester to a derivative of (−)-2-hydroxy-1-phenyl-1-propanone, which has already been shown to have S-configuration. Metabolism of tamoxifen by rat liver microsomes gave equal amounts of the two enantiomers. They have the same chemical properties but, on treatment of rat hepatocytes in culture, R-(+)-α-hydroxytamoxifen gave at least eight times as many DNA adducts as the S-(−)-isomer.
We study Hotelling's two-stage model of spatial competition, in which two firms first simultaneously choose locations in the unit interval, then simultaneously choose prices. Under Hotelling's ...assumptions (uniform distribution of consumers, travel cost proportional to distance, inelastic demand of one unit by each consumer) the price-setting subgames possess equilibria in pure strategies for only a limited set of location pairs. Because of this problem (pointed out independently by Vickrey (1964) and d'Aspremont et al. (1979)), Hotelling's claim that there is an equilibrium of the two-stage game in which the firms locate close to each other is incorrect. A result of Dasgupta and Maskin (1986) guarantees that each price-setting subgame has an equilibrium in mixed strategies. We first study these mixed strategy equilibria. We are unable to provide a complete characterization of them, although we show that for a subset of location pairs all equilibria are of a certain type. We reduce the problem of finding an equilibrium of this type to that of solving three or fewer highly nonlinear equations. At each of a large number of location pairs we have computed approximate solutions to the system of equations. Next, we use our analytical results and computations to study the equilibrium location choices of the firms. There is a unique (up to symmetry) subgame perfect equilibrium in which the location choices of the firms are pure; in it, the firms locate 0.27 from the ends of the market. At this equilibrium, the support of the subgame equilibrium price strategy is the union of two short intervals. Most of the probability weight is in the upper interval, so that this strategy is reminiscent of occasional "sales" by the firms. We also find a subgame perfect equilibrium in which each firm uses a mixed strategy in locations. In fact, in the class of strategy pairs in which the firms use the same mixed strategy over locations, and this strategy is symmetric about .5, there is a single equilibrium. In this equilibrium most of the probability weight of the common strategy is between 0.2 and 0.4, and between 0.6 and 0.8. There is a wide range of pure Nash (as opposed to subgame perfect) equilibrium location pairs: the subgame strategies in which each firm threatens to charge a price of zero in response to a deviation support all but those location pairs in which the firms are very close.
Ozone is an important factor in urban pollution and represents a major concern for human health. The chemical reactivity of ozone toward biological targets and particularly its genotoxicity supports ...a possible link between exposure and cancer risk, but no molecular data exist on its mutagenic potential in human cells. Using a shuttle vector, we showed that ozone is indeed a potent mutagen and we characterized the mutation spectrum it produced in human cells. Almost all mutations are base substitutions, essentially located at G:Cs (75%), typical of reactive oxygen species (ROS), but occurring in a specific pattern, i.e. a similar extent of GC:TA (28%), GC:CG (23%) and GC:AT (23%). The targeted distribution of mutations and identification of hotspot sequences define the first molecular fingerprint of mutations induced by ozone in human cells. Possible applications derived from our results with respect to ozone genotoxicity should help determining quantifiable biomarkers of ozone exposure in human health, especially for carcinogenesis.
Game-theoretic reasoning pervades economic theory and is used widely in other social and behavioural sciences. An Introduction to Game Theory International Edition, by Martin J. Osborne, presents the ...main principles of game theory and shows how they can be used to understand economics, social, political, and biological phenomena. The book introduces in an accessible manner the main ideas behind the theory rather than their mathematical expression. All concepts are defined precisely, and logical reasoning is used throughout. The book requires an understanding of basic mathematics but assumes no specific knowledge of economics, political science, or other social or behavioural sciences. Coverage includes the fundamental concepts of strategic games, extensive games with perfect information, and coalitional games; the more advanced subjects of Bayesian games and extensive games with imperfect information; and the topics of repeated games, bargaining theory, evolutionary equilibrium, rationalizability, and maxminimization. The book offers a wide variety of illustrations from the social and behavioural sciences. Each topic features examples that highlight theoretical points and illustrations that demonstrate how the theory may be used.
Tamoxifen (E)-1-(4-(2-(N,N-dimethylamino)ethoxy)phenyl)-1,2-diphenylbut-1-ene, a nonsteroidal antiestrogen, induces liver tumors in rats by a genotoxic mechanism. The mechanism of DNA adduct ...formation is believed to proceed via the formation of a reactive carbocation at the α-position from the α-hydroxylated metabolite. Molecular mechanics calculations Kuramochi, H. (1996) J. Med. Chem. 39, 2877−2886 have predicted that 4-substitution will affect the stability of the carbocation and thus will alter its reactivity toward DNA. We have synthesized the putative α-hydroxylated metabolites of 4-hydroxytamoxifen (E)-1-(4-(2-(N,N-dimethylamino)ethoxy)phenyl)-1-(4-hydroxyphenyl)-3-hydroxy-2-phenylbut-1-ene and idoxifene (Z)-1-(4-iodophenyl)-3-hydroxy-2-phenyl-1-(4-(2-( N-pyrrolidino)ethoxy)phenyl)but-1-ene and compared their reactivities with DNA with that of α-hydroxytamoxifen (E)-1-(4-(2-(N,N-dimethylamino)ethoxy)phenyl)-3-hydroxy-1,2-diphenylbut-1-ene. As predicted, the bis-hydroxylated compound reacted with DNA in aqueous solution at pH 5 to give 12-fold greater levels of adducts than α-hydroxytamoxifen, whereas α-hydroxyidoxifene gave one-half the number of adducts. The results demonstrate that idoxifene presents a significantly lower genotoxic hazard than tamoxifen for the treatment and prophylaxis of breast cancer.
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