Studies of the genetic regulation involved in drug metabolizing enzymes and drug transporters are of great interest to understand the molecular mechanisms of drug response and toxic events. Recent reports have revealed that hydrophobic ligands and several nuclear receptors are involved in the induction or down-regulation of various enzymes and transporters involved in Phase I, II, and III xenobiotic metabolizing systems. Nuclear receptors (NRs) form a family of ligand-activated transcription factors (TFs). These proteins modulate the regulation of target genes by contacting their promoter or enhancer sequences at specific recognition sites. These target genes include metabolizing enzymes such as cytochrome P450s (CYPs), transporters, and NRs. Thus it was now recognized that these NRs play essential role in sensing processing xenobiotic substances including drugs, environmental chemical pollutants and nutritional ingredients. From literature, we picked up target genes of each NR in xenobiotic response systems. Possible cross-talk, by which xenobiotics may exert undesirable effects, was listed. For example, the role of NRs was comprehensively drawn up in cholesterol and bile acid homeostasis in human hepatocyte. Summarizing current states of related research, especially for in silico response element search, we tried to elucidate nuclear receptor mediated xenobiotic processing loops and direct future research.

The probes to detect vesicular acetylcholine transporter (VAChT) in vivo are important to evaluate the mapping and function in cholinergic system. To develop high‐specific and high‐affinity radiotracer for single photon emission computed tomography, we investigated piperazine analogs which replaced the piperidine ring of (‐)‐vesamicol with a piperazine ring. We found that the piperazine analog of iodobenzovesamicol, trans‐5‐iodo‐2‐hydroxy‐3‐[4‐phenylpiperazinyl] tetralin (DRC140), had high affinity for VAChT in rat brain. We carried out binding assay in subcellular fraction of the rat brain. The highest Bmax for [125I]‐DRC140 binding was observed in the synaptic vesicle fraction (1,751 fmol/mg protein), followed by the crude vesicle (821 fmol/mg protein) and the P2 fraction (187 fmol/mg protein). These Kd values were similar to the affinity of highly purified synaptic vesicular fraction (Kd = 0.3 nM) with a one‐site model. The possibility that [125I]‐DRC140 recognizes sigma receptor was excluded by our finding large inhibition constants (Ki = 849 nM for haloperidol, Ki = 3,052 nM for 1,3‐di(2‐tolyl)guanidine). In vivo distribution studies with the [123I]‐DRC140 in rats showed a rapid brain uptake. The highest brain area was in striatum, followed by frontal cortex, occipital cortex, and hippocampus. The lowest brain area was cerebellum. The radioactivity of high‐accumulated areas in ex vivo autoradiography was reduced by a preinjection of (‐)‐vesamicol and these levels were reduced to the radioactivity in cerebellum. These results show that [125I]‐DRC140 can provide extremely high specific tracer with excellent brain permeability as a ligand for single photon emission computed tomography. Synapse 38:27–37, 2000. © 2000 Wiley‐Liss, Inc.

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Square-planar complexes with the formula [Pt(L1) (L2)]X2, where L1 is di(ammine) or 2,2′-bipyridine (bpy) or 1,10-phenanthroline (phen) and L2 is N-ethyl-1,2-ethanediamine (Eten) or N-benzyl-1,2-ethanediamine (Been), and X = NO3- or Cl-, were prepared. NMR measurements of D2O solutions of these complexes showed that the N-ethyl and N-benzyl groups are forced to take a pseudo axial disposition due to an intramolecular repulsion from hydrogen atoms of aromatic diamines for complexes where L1 = bpy or phen and significant upfield shifts due to the ring current effect were observed for the Been complexes. An analysis of coupling with N-H and 195Pt showed that the major rotamer due to rotation around CH2-NH is (-)-syn for the Been with a significant intramolecular stacking between aromatic rings of L1 and L2, but anti- for the Eten complexes. The solvent and temperature dependency of the upfield shift of the Been complexes are described; the protein denaturants, guanidinium chloride, and urea, act to reduce stacking as dioxane.

The spectroscopic properties of platinum(II) complexes with 2-aminomethyl-derivatives of small-membered 1-aza-cycloalkane, i.e., ‫-2؍‬aminomethylaziridine‫؍‬azida and S-2-aminomethylazetidine‫؍‬S-azeda, and the crystal structures of their dichloro complexes demonstrate that the conformation of the fused three-(azida) or four-(Sazeda) and five-membered chelate ring formed by the coordination of S-azida and S-azeda to platinum(II) has an S(N) absolute configuration at the secondary amine site and that the two alkyl groups extend axially from the five-membered chelate ring. The chelate ring of the azida is more planar than the S-azeda or other 2-aminomethyl-1-azacycloalkanes. The anticancer activity reported for azeda and 2-aminomethylpyrrolidine appears to be related to their coordination structure, namely the presence of cis-fused successive rings.