Decoding of UGA selenocysteine codons in eubacteria is mediated by the specialized elongation factor SelB, which conveys the charged tRNASec to the A site of the ribosome, through binding to the SECIS mRNA hairpin. In an attempt to isolate the eukaryotic homolog of SelB, a database search in this work identified a mouse expressed sequence tag containing the complete cDNA encoding a novel protein of 583 amino acids, which we called mSelB. Several lines of evidence enabled us to establish that mSelB is the bona fide mammalian elongation factor for selenoprotein translation: it binds GTP, recognizes the Sec‐tRNASec in vitro and in vivo, and is required for efficient selenoprotein translation in vivo. In contrast to the eubacterial SelB, the recombinant mSelB alone is unable to bind specifically the eukaryotic SECIS RNA hairpin. However, complementation with HeLa cell extracts led to the formation of a SECIS‐dependent complex containing mSelB and at least another factor. Therefore, the role carried out by a single elongation factor in eubacterial selenoprotein translation is devoted to two or more specialized proteins in eukaryotes.

Many administered drugs are first activated by phase I drug-metabolizing enzymes, such as cytochrome P450 (CYP), and then conjugated with ligands such as UDPGA, PAPS, and glutathione by phase II drug-metabolizing enzymes, and finally excreted by transporters. There are some defective activity mutants due to CYP polymorphisms. In these cases, drugs are not metabolized [poor metabolizer (PM)], the high drug levels in blood are maintained, and toxic effects appear in the patients. To clarify the ratio of PMs, in the general population, it is necessary to estimate the drug level to not only prevent toxic reactions, but also to provide more efficient drug therapies, according to their polymorphic information about CYPs. In Caucasians and Asians, PM and allele frequency levels of CYPs (CYP2A6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) are summarized from previous findings. In Caucasians, high PM ratios (7%) of CYP2D6 deriving from the high frequency of CYP2D6*4 and CYP2D6*5, and 2% CYP2C19 from CYP2C19*2, were found. Meanwhile, in Asians, high PM ratios (19%) of CYP2C19 from high frequencies of CYP2C19*2 and CYP2C19*3, and 2% to 4% CYP2A6 from CYP2A6*4, were found. In both populations, the PM frequencies of the CYP3A4 of major drug-metabolizing CYP and CYP2C9 were low.

P-glycoprotein (P-gp, ABCB1, MDR1) was recognized as a drug-exporting protein from cancer cells three decade ago. Apart from the multidrug transporter side effects of P-gp, normal physiological functions of P-gp have been reported. P-gp could be responsible for translocating platelet-activating factor (PAF) across the plasma membrane and PAF inhibited drug transport mediated by P-gp in cancer cells. P-gp regulated the translocation of sphingomyelin (SM) and GlcCer, and short chain C(6)-NBD-GlcCer was found in the apical medium of P-gp cells exclusively and not in the basolateral membrane. SM plays an important role in the esterification of cholesterol. High expression of P-gp prevents stem-cell differentiation, leading to the proliferation and amplification of this cell repertoire, and functional P-gp plays a fundamental role in regulating programmed cell death, apoptosis. The transporter function of P-gp is therefore necessary to protect cells from death. P-gp can translocate both C(6)-NBD-PC and C(6)-NBD-PE across the apical membrane. This PC translocation was also confirmed with [(3)H]choline radioactivity. Progesterone is not transported by P-gp, but blocks P-gp-mediated efflux of other drugs and P-gp can mediate the transport of a variety of steroids. Cells transfected with human P-gp esterified more cholesterol. P-gp might also be involved in the transport of cytokines, particularly IL-1beta, IL-2, IL-4 and IFNgamma, out of activated normal lymphocytes into the surrounding medium. P-gp expression is also associated with a volume-activated chloride channel, thus P-gp is bifunctional with both transport and channel regulators. We also present information about P-gp polymorphism and new structural concepts, "gate" and "twist", of the P-gp structure.

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The serum concentration of valproic acid (VPA) in epilepsy patients decreased by the administration of carbapenem antibiotics, such as meropenem, panipenem or imipenem, to a sub-therapeutic level. This review summarized several case reports of this interaction between VPA (1-4 g dose) and carbapenem antibiotics to elucidate the possible mechanisms decreasing VPA concentration by carbapenem antibiotics. Studies to explain the decrease were carried out using rats by the following sites: absorption of VPA in the intestine, glucuronidation in the liver, disposition in blood and renal excretion. In the intestinal absorption site, there are two possible mechanisms: inhibition of the intestinal transporter for VPA absorption by carbapenem antibiotics, and the decrease of beta-glucuronidase supplied from enteric bacteria, which were killed by antibiotics. This is consistent with a view that the decrease of VPA originated from VPA-Glu, relating to entero-hepatic circulation. The second key site is in the liver, because of no decreased in VPA level by carbapenem antibiotics in hepatectomized rats. There are three possible mechanisms in the liver to explain the decreased phenomenon: first, decrease of the UDPGA level by carbapenem antibiotics. UDPGA is a co-factor for UDP-glucuronosyltransferase (UGT)-mediated glucuronidation of VPA. Second, the direct activation of UGT by carbapenem antibiotics. This activation was observed after pre-incubation of human liver microsomes with carbapenem antibiotics. Third, the inhibition of beta-glucuronidase in liver by carbapenem antibiotics and the decreased VPA amount liberated from VPA-Glu. The third site is the distribution of VPA in blood (erythrocytes and plasma). Plasma VPA distributed to erythrocytes by the inhibition of transporters (Mrp4), which efflux VPA from erythrocytes to plasma, by carbapenem antibiotics. The increase of renal excretion of VPA as VPA-Glu depends on the increase of VPA-Glu level by UGT. One or a combination of some factors in these mechanisms might relate to the carbapenem-mediated decrease of the plasma VPA level.