The Modulation of Phase II Drug-Metabolizing Enzymes in Proliferating and Differentiated CaCo-2 Cells by Hop-Derived Prenylflavonoids.

Prenylflavonoids in the human organism exhibit various health-beneficial activities, although they may interfere with drugs via the modulation of the expression and/or activity of drug-metabolizing enzymes. As intestinal cells are exposed to the highest concentrations of prenylflavonoids, we decided to study the cytotoxicity and modulatory effects of the four main hop-derived prenylflavonoids on the activities and mRNA expression of the main drug-conjugating enzymes in human CaCo-2 cells. Proliferating CaCo-2 cells were used for these purposes as a model of colorectal cancer cells, and differentiated CaCo-2 cells were used as an enterocyte-like model. All the tested prenylflavonoids inhibited the CaCo-2 cells proliferation, with xanthohumol proving the most effective (IC50 8.5 µM). The prenylflavonoids modulated the activities and expressions of the studied enzymes to a greater extent in the differentiated, as opposed to the proliferating, CaCo-2 cells. In the differentiated cells, all the prenylflavonoids caused a marked increase in glutathione S-transferase and catechol-O-methyltransferase activities, while the activity of sulfotransferase was significantly inhibited. Moreover, the prenylflavonoids upregulated the mRNA expression of uridine diphosphate (UDP)-glucuronosyl transferase 1A6 and downregulated that of glutathione S-transferase 1A1/2.

Prenylflavones from Psoralea corylifolia inhibit nitric oxide synthase expression through the inhibition of I-kappaB-alpha degradation in activated microglial cells.

The overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) switches the function of NO from a physiological neuromodulator to a neurotoxic effector in central nervous system (CNS) after brain injury. From the methanol extracts of Psoralea corylifolia, we purified two inhibitors of NO production in lipopolysaccharide (LPS)-activated microglia by activity guided purification along with two inactive compounds. The active compounds were identified as a chromenoflavanone [7,8-dihydro-8-(4-hydroxyphenyl)-2,2-dimethyl-2H,6H-benzo-(1,2-b:5,4-b')dipyran-6-one] (1) and 4-hydroxylonchocarpin (2). And the inactive two compounds were identified as bavachinin (3) and bavachalcone (4) by spectral analysis. The compound 2 was isolated first time from this plant. Compounds 1 and 2 inhibited the production of NO in LPS-activated microglia in a dose dependent manner (IC(50)'s were 11.4, 10.2 microM, respectively). They also suppressed the expression of protein and mRNA of iNOS in LPS-activated microglial cells at 10 muM as observed in Western blot analysis and RT-PCR experiment. Furthermore they inhibited the degradation of I-kappaB-alpha in activated microglia. These results imply that compounds 1 and 2 can be lead compounds for the development of neuroprotective drug with the inhibitory activity of NO overproduction by activated microglial cells.

Manufacture and use of chloroprene monomer.

There are only six manufacturers of chloroprene (CD) located outside of the former Communist Bloc countries. Five of these manufacture chloroprene from butadiene via a two step process consisting of chlorination and subsequent dehydrochlorination. The sixth dimerizes acetylene and then hydrochlorinates the dimer to produce CD. Both the acetylene and butadiene-based manufacturing processes are conducted within sealed systems. Therefore, the only potential exposure during manufacture is sampling for product quality, strainer/filter changing and accidental leaks or spills. All six manufacturers produce CD only for the production of polymer. Manufacturers convert CD into polychloroprene polymer (PCP) via emulsion polymerization. A solution of CD and other ingredients is mixed with an aqueous caustic solution to produce an emulsion. Free radicals initiate polymerization and free radical scavengers are added to stop the reaction at the desired conversion. After unreacted monomer is removed, PCP can be sold as a latex (colloid) or isolated and dried to produce solid product. The PCP manufacturing process is also designed to be a closed system. However, the extreme reactivity of CD and the inherent stickiness of PCP polymer, makes it necessary to 'open' the process to remove polymer. This results in potential for operator exposure, in addition to the items mentioned for CD manufacture. With the use of appropriate engineering controls, work practices and personal protective equipment for activities with exposure potential, actual workplace exposures are controlled below the occupational exposure limits (2-10 ppm). The solid PCP products, which comprise approximately 92% of the total amount of polymer manufactured, contain <1 ppm CD. Most PCP latexes contain <0.1% residual CD. So, the potential for CD industrial exposure is limited to CD and PCP manufacture.