Adenine suppresses IgE-mediated mast cell activation.

Nucleobase adenine is produced by dividing human lymphoblasts mainly from polyamine synthesis and inhibits immunological functions of lymphocytes. We investigated the anti-allergic effect of adenine on IgE-mediated mast cell activation in vitro and passive cutaneous anaphylaxis (PCA) in mice. Intraperitoneal injection of adenine to IgE-sensitized mice attenuated IgE-mediated PCA reaction in a dose dependent manner, resulting in a median effective concentration of 4.21 mg/kg. In mast cell cultures, only adenine among cytosine, adenine, adenosine, ADP and ATP dose-dependently suppressed FcɛRI (a high affinity receptor for IgE)-mediated degranulation with a median inhibitory concentration of 1.6mM. It also blocked the production of LTB4, an inflammatory lipid mediator, and inflammatory cytokines TNF-α and IL-4. In addition, adenine blocked thapsigargin-induced degranulation which is FcɛRI-independent but shares FcɛRI-dependent signaling events. Adenine inhibited the phosphorylation of signaling molecules important to FcɛRI-mediated allergic reactions such as Syk, PLCγ2, Gab2, Akt, and mitogen activated protein kinases ERK and JNK. From this result, we report for the first time that adenine inhibits PCA in mice and allergic reaction by inhibiting FcɛRI-mediated signaling events in mast cells. Therefore, adenine may be useful for the treatment of mast cell-mediated allergic diseases. Also, the upregulation of adenine production may provide another mechanism for suppressing mast cell activity especially at inflammatory sites.

In vivo absorption, distribution, excretion, and metabolism of a new herbicide, methiozolin, in rats following oral administration.

Methiozolin [5-(2,6-difluorobenzyl)oxymethyl-5-methyl-3-(3-methylthiophen-2-yl)-1,2-isoxazoline] is a new turf herbicide that controls annual bluegrass in various cool- and warm-season turfgrasses. The present study is the first report elucidating absorption, tissue distribution, excretion, and metabolism of methiozolin in rats. The pharmacokinetic parameters in the blood were observed as follows: t(max) = 6 h, C(max) = 168.7 µg equiv/mL, t(½) = 49.4 h, AUC120 = 9921.5 µg equiv·h/mL, and clearance = 39.2 mL/h/kg. Those parameters and the depletion curve for ¹4C in the plasma were very similar to those in the blood. Total excretion through urine and feces was 24.3 and 68.9%, respectively, during 120 h after administration; however, there was no excretion through expired air. The radioactivity excreted through bile was 40.1% of that administered. Excreted radioactivity peaked between 24 and 48 h, showing 51.0% of total excretion within 48 h. The orally administered ¹4C distributed across various tissues within 12 h after administration, showing 14.0% of the dosed, and was eliminated from all tissues without accumulation. Numerous minor metabolites (<4% of the dosed) in urine and fecal extract were detected within 72 h, and two of those were identified. The identified metabolites were Met-1 (glucuronic acid conjugate), 6-[5-(5-((2,6-difluorobenzyloxy)methyl)-4,5-dihydro-5-methylisoxazol-3-yl)-4-methylthiophen-2-yloxy]-tetrahydro-3,4,5-trihydroxy-2H-pyran-2-carboxylic acid, and Met-2, [2-(5-((2,6-difluorobenzyloxy)methyl)-4,5-dihydro-5-methylisoxazol-3-yl)thiophen-3-yl]methanol. Conclusively, methiozolin was shown to be readily absorbed in the gastrointestinal tract, distributed throughout the tissues within 12 h, metabolized extensively, and eliminated through urine and feces mostly within 48 h, without tissue accumulation.