The absorption, distribution and excretion of most of xenobiotics, drugs, environmental toxins and their metabolites are mediated by membrane transporters. Recent advances in the transporter molecular biology have made it possible to investigate the mechanisms of transport of those exogenous compounds and their transporter-mediated toxicity at the molecular level. Exogenous compounds including drugs and toxic substances occurring in the environment pass through the transporters with broad substrate selectivity, namely "multispecific" transporters, taking advantage of the multispecific nature to exert their toxic effects. The remarkable examples of such transporter-mediated toxicity are 1-methyl-4-phenyl-2,3-dihydropyridinium (MPP+)-neurotoxicity mediated by dopamine transporters, cephaloridine-nephrotoxicity mediated by organic anion transporters and methylmercury-toxicity mediated by system L amino acid transporters. The molecular identification of system L transporter LAT1 (L-type amino acid transporter 1) has lead to the understanding of the mechanisms of their multispecific substrate recognition and revealed their localization at the blood-brain barrier and placental barrier. LAT1 relies on the hydrophobic interaction between substrate amino acid side chains and the substrate binding site, so that many variations are possible for the substrate amino acid side chains, which is the basis of the broad substrate selectivity. System L transporters, thus, function as a path for the membrane permeation of drugs and toxic compounds occurring in the environment with amino acid-related structures. Beside methylmercury-cysteine conjugate, amino acid-related neurotoxins such as β-N-methylamino-L-alanine, S-(1,2-dichlorovinyl)-L-cysteine and 3-hydroxykynurenine are proposed to pass through system L transporters to exert their toxicity. Because the presence of such transporters is crucial for the manifestation of the organ toxicity, the inhibition of the transporters would be expected to be beneficial to prevent the disorders caused by the transporter-mediated toxicity.
Skin sensitization potential of low molecular weight chemicals was assessed by analyzing peptide-conjugate formation. Chemicals were incubated with a peptide, glutathione, and resultant mixtures were analyzed by mass spectrometry. Eighteen chemicals were assessed, and new peaks corresponding to chemical-peptide conjugates were detected for 13 of 14 known sensitizers. Conjugates were not detected for 4 negative chemicals. The method has advantages as a simple screening assay for assessing the sensitization potential of chemicals.
This study examined a low-molecular-weight factor-Xa inhibitor, KFA-1411 (3-[N-(3-amidinophenyl)-N-[N-[4-[1-(1-iminoethyl)piperidin-4-yl]phenyl]carbamoylmethyl]aminomethyl]phenoxyacetic acid monosulfonate·dihydrate). KFA-1411 selectively inhibited FXa among the serine proteases in the human blood-coagulation cascade with a Ki value of 1.73 nM, (selectivity ratio, 15000 versus its action on thrombin). The anticoagulant action of KFA-1411 in human plasma almost equaled that of the selective thrombin inhibitor, argatroban. KFA-1411 did not inhibit platelet aggregation at the concentration at which it showed an anticoagulant action. In contrast, argatroban, heparin, and low-molecular-weight heparin (LMWH; dalteparin) inhibited thrombin-induced platelet aggregation at concentrations lower than those needed for their anticoagulant actions. The FXa-inhibiting action of KFA-1411 differed among animal species, the maximum effect being seen in humans, followed by monkeys and rabbits, with rats and mice showing about one-tenth the potency seen in humans. A species variation was also observed among the values obtained for KFA-1411 in respect of anticoagulant activity in plasma (monkeys again being closest to humans). These results indicate that KFA-1411 may exhibit antithrombotic efficacy without an unwanted platelet-related action in the future treatment of various thrombotic diseases. The experimental model of monkeys is recommended for estimation of the clinical effects and safety of KFA-1411 in humans.
The effects of garenoxacin (formerly T-3811 or BMS-284756) on the central nervous system (CNS) were compared with various quinolones. Garenoxacin injected intracerebroventricularly into mice caused clonic convulsion at a higher dose (50 μg/body) than norfloxacin, ciprofloxacin, sitafloxacin and trovafloxacin. Additionally the convulsant activity of garenoxacin was not potentiated by biphenylacetic acid (BPAA). Garenoxacin did not induce any convulsions at intravenous doses up to 60 mg/kg in combination with 200 mg/kg oral administration of fenbufen in mice, and its convulsant activity was weaker than those of enoxacin, norfloxacin, ciprofloxacin, alatrofloxacin and ofloxacin. In addition, convulsions were not induced by combination administration of garenoxacin (60 mg/kg, i.v.) and any of 9 kinds of nonsteroidal anti-inflammatory drugs (NSAIDs) or BPAA. In a rotarod test, which was performed in order to evaluate the drug-induced dizziness, coordinated locomotor activity of mice was suppressed by alatrofloxacin at an intravenous dose of 60 mg/kg, but not by garenoxacin, ciprofloxacin and norfloxacin at up to 60 mg/kg. In an in vitro study using rat brain synaptic membrane, garenoxacin had no inhibitory effect on GABA binding in the presence or absence of NSAIDs. In conclusion, the effects of garenoxacin on CNS were weaker than those of other quinolones in experimental animals, so it might possess a low potential for CNS adverse reactions such as convulsion and dizziness in clinical use.