Objectives The objective of this metallomics study is to investigate comprehensively some relationships between cancer risk and minerals, including essential and toxic metals. Methods Twenty-four minerals including essential and toxic metals in scalp hair samples from 124 solid-cancer patients and 86 control subjects were measured with inductively coupled plasma mass spectrometry (ICP-MS), and the association of cancer with minerals was statistically analyzed with multiple logistic regression analysis. Results Multiple logistic regression analysis demonstrated that several minerals are significantly correlated to cancer, positively or inversely. The most cancer-correlated mineral was iodine (I) with the highest correlation coefficient of r = 0.301, followed by arsenic (As; r = 0.267), zinc (Zn; r = 0.261), and sodium (Na; r = 0.190), with p \ 0.01 for each case. In contrast, selenium (Se) was inversely correlated to cancer (r = -0.161, p \ 0.05), followed by vanadium (V) (r = -0.128). Multiple linear regression value was highly significantly correlated with probability of cancer (R 2 = 0.437, p \ 0.0001), and the area under the receiver-operating characteristic (ROC) curve was calculated to be 0.918. In addition, using contingency table analysis and the chi-square test, the precision of discrimination for cancer was estimated to be 0.871 (chi-square = 99.1, p \ 0.0001). Conclusions These findings suggest that some minerals such as arsenic, selenium, and probably iodine, zinc, sodium, and vanadium contribute to regulation of cancer and also that metallomics study using multiple logistic regression analysis is a useful tool for estimating cancer risk.

A series of 4-(2-methylimidazol-1-yl)-2,2-diphenylbutyramide derivatives was prepared as part of a search for subtype-selective antimuscarinic agents. On the basis of measurements of the antimuscarinic activity and subtype-selectivity for M2 and M3 muscarinic receptors, the structure-activity relationships of these compounds are discussed.

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Imidafenacin (CAS 170105-16-5, KRP-197, ONO-8025) is an antagonist for the muscarinic acetylcholine (ACh) receptor currently under development for the treatment of overactive bladder. Affinities of imidafenacin and other drugs for muscarinic ACh receptor subtypes were investigated by examining inhibitory effects on ACh release in the rat urinary bladder and K+ efflux in the rat salivary gland in functional and binding assays. In the functional assay, imidafenacin had higher affnities for M3 and M1 receptors than for the M2 receptor. In contrast, metabolites of imidafenacin (M-2, M-4 and M-9) had low affinities for muscarinic ACh receptor subtypes. Darifenacin had selectivity for the M3 receptor, while propiverine, tolterodine and oxybutynin had no selectivity for muscarinic ACh receptors. In carbamylcholine (CCh)-induced contraction in the urinary bladder, imidafenacin, propiverine, tolterodine and oxybutynin had affinities similar to those for the M3 receptor in the ileum. In the binding assay for human muscarinic ACh receptor subtypes, imidafenacin had higher affinities for m3 and m1 receptors than for m2 receptor, but tolterodine had no selectivity for m1, m2 and m3 receptors. In ACh release in the urinary bladder, inhibitory effects of imidafenacin, tolterodine, oxybutynin and darifenacin seemed to be partially mediated by the M1 receptor. In ACh-induced and electrical stimulation-induced K+ efflux from the salivary gland, inhibitory effects (IC50) of imidafenacin, propiverine, tolterodine, oxybutynin and darifenacin might be closely related to those for the M3 receptor in the ileum. These results suggest that imidafenacin more strongly antagonizes cholinomimetics on M3 and M1 receptors than on the M2 receptor. Moreover, imidafenacin seems to inhibit the contraction of the bladder smooth muscle by mediating antagonism to the M3 receptor and to regulate ACh release by mediating prejunctional facilitatory M1 receptor. Imidafenacin also inhibited K+ efflux from the salivary gland mainly by mediating the M3 receptor. Therefore, imidafenacin will have higher affinities for M3 and M1 receptors and higher selectivity for the urinary bladder than for the salivary gland.

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