No abstract

No abstract

The possibility that beer and other alcoholic beverages could be antimutagenic against the heterocyclic amines (HAs), a group of carcinogens produced on cooking proteinaceous foods, has been explored. In the Salmonella mutation assays, beer showed inhibitory effects against several HAs [preactivated Trp-P-1, Trp-P-2(NHOH), and Glu-P-1(NHOH)] that are directly mutagenic in bacteria. Japanese sake, red and white wines, and brandy were also effective. However, ethyl alcohol alone did not show these effects. The formation of O(6)-methylguanine by N-methyl-N'-nitro-N-nitrosoguanidine in the DNA of Salmonella YG7108 was also inhibited by beer. Nonvolatile beer components were administered orally to CDF(1) mice together with Trp-P-2. Adducts in the liver DNA were significantly decreased by the beer, as compared to those in controls fed Trp-P-2 only. Although several phenolic compounds known to be present in beer were antimutagenic toward these mutagens, their effects were very small. It was concluded that some yet to be identified component(s) of beer is (are) responsible for this antimutagenicity.

We previously reported RXR partial agonist CBt-PMN (1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid: 5, EC50 = 143 nM, Emax = 75%), which showed a potent glucose-lowering effect without causing serious adverse effects. However, it remains important to elucidate the structural requirements for RXR efficacy and the glucose-lowering effect because RXR-permissive heterodimers such as PPAR/RXR or LXR/RXR are reported to be activated differently depending upon the chemical structure of RXR agonists. In this work, we show that an RXR partial agonist, NEt-4IB (6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: 8b, EC50 = 169 nM, Emax = 55%), can be obtained simply by repositioning the side chains (interchanging the isobutoxy and isopropoxy groups) at the hydrophobic moiety of the RXR full agonist NEt-3IB (6-[ethyl-(3-isobutoxy-4-isopropylphenyl)amino]pyridine-3-carboxylic acid: 7b, EC50 = 19 nM). NEt-4IB (8b) showed antitype 2 diabetes activity without the above side effects upon repeated oral administration to mice at 10 mg/kg/day, similarly to 5.

No abstract