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Functional influence of human CYP2D6 allelic variations: P34S, E418K, S486T, and R296C
김주환,임영란,한송희,한정수,천영진,윤철호,이창훈,김동학 대한약학회 2013 Archives of Pharmacal Research Vol.36 No.12
CYP2D6 is responsible for the oxidativemetabolism of 20–25 % of clinical drugs and its geneticpolymorphisms can significantly influence the drugmetabolism. In this study, we analyzed the functionalactivities of four nonsynonymous single nucleotide polymorphismsfrom CYP2D6*52 allele, which were recentlyfound, and one found frequently in CYP2D6 alleles. Recombinant variant enzymes of E418K, S486T, andR296C were successfully expressed in Escherichia coli andpurified. However, a CYP holoenzyme spectrum of P34Svariant was not detected in E. coli whole cell level. Structural analysis indicated that P34S mutation seemed toperturb a highly conserved proline-rich N-terminus ofCYP2D6. Steady state kinetic analyses showed the significantreductions of enzymatic activities in E418K andR296C variants. In the case of bufuralol 1’-hydroxylation,a novel mutant, E418K, showed 32 % decrease in catalyticefficiency (kcat/Km) mainly due to the decrease of kcatvalue. R296C showed much greater reduction in the catalyticefficiency (9 % of wild-type) due to both of a decrease of kcat value and an increase of Km value. In the case ofdextromethorphan O-demethylation, E418K showed bothof a decrease of kcat value and an increase Km value toresult in *43 % reduction of catalytic efficiency. A highlydecreased catalytic efficiency (*6 % of wild-type) in themutant of R296C also was observed mainly due to thedramatic change of kcat value of dextromethorphanO-demethylation. These results suggested that individualscarrying these allelic variants are likely to have the alteredmetabolic abilities of many clinical drugs therefore, thesepolymorphisms of CYP2D6 should be much concerned forreliable drug treatment.
김주환,이수은,강소희,전태일,강만종,이태훈,김용식,김기선,임혜인,문창종 한국분자세포생물학회 2018 Molecules and cells Vol.41 No.5
Crosstalk between G-protein signaling and glutamatergic transmission within the brain reward circuits is critical for long-term emotional effects (depression and anxiety), cravings, and negative withdrawal symptoms associated with opioid addiction. A previous study showed that Regulator of G-protein signaling 4 (RGS4) may be implicated in opiate action in the nucleus accumbens (NAc). However, the mechanism of the NAc-specific RGS4 actions that induce the behavioral responses to opiates remains largely unknown. The present study used a short hairpin RNA (shRNA)-mediated knock-down of RGS4 in the NAc of the mouse brain to investigate the relationship between the activation of ionotropic glutamate receptors and RGS4 in the NAc during morphine reward. Additionally, the shRNA-mediated RGS4 knock-down was implemented in NAc/striatal primary-cultured neurons to investigate the role that striatal neurons have in the mor-phine-induced activation of ionotropic glutamate receptors. The results of this study show that the NAc-specific knock-down of RGS4 significantly increased the behaviors associated with morphine and did so by phosphorylation of the GluR1 (Ser831) and NR2A (Tyr1325) glutamate receptors in the NAc. Furthermore, the knock-down of RGS4 enhanced the phosphorylation of the GluR1 and NR2A glutamate receptors in the primary NAc/striatal neurons during spontaneous morphine withdrawal. These findings show a novel molecular mechanism of RGS4 in glutamatergic transmission that underlies the negative symptoms associated with morphine administration.
풋백옵션제도 폐지가 IPO 공모가격 및 장단기 주가성과에 미친 영향
김주환,박진우 한국산업경제학회 2016 한국산업경제학회 정기학술발표대회 논문집 Vol.2016 No.5
본 논문에서는 풋백옵션제도 폐지가 개인투자자 매매행태와 투자성과에 미친 영향을 살펴보고, 특히 상장 이후 공모가 이하로 가격이 하락한 IPO 주식에서 개인투자자의 손실을 분석하고 있다. 분석결과는 다음과 같다. 첫째, 공모가조정률을 종속변수로 한 회귀분석 결과, IPO 직전의 시장상황, 기관 경쟁률, 희망공모가 범위 등 수요예측 정보가 공모가 결정에 유의미한 영향을 미치고 있으며 특히 풋백옵션제도 폐지는 공모가조정률을 증가시키고 있다. 둘째, 공모가조정률은 풋백옵션제도 폐지 전후 기간에서 IPO 초기수익률에 유의미한 양(+)의 영향을 미치고 있다. 셋째, 풋백옵션제도 폐지는 IPO 초기수익률에 유의미한 음(-)의 영향을 미치고 있다. 넷째, 풋백옵션제도 폐지 전후 기간에서 개인청약 경쟁률은 IPO 초기수익률에 유의미한 양(+)의 영향을 미치고 있으며 이후 장기저성과를 보이고 있다. 다섯째, 상장후 20일 누적 개인순매수비율은 이후 IPO 장기성과에 유의미한 영향을 미치고 있지 않으나, 풋백옵션제도 폐지 이후에 공모가 이하 표본수 비율이 크게 증가하고 20일 누적 개인순매수비율이 증가하여 상장 직후 집중적으로 IPO주식을 순매수한 개인투자자가 시장에서 큰 손실을 입는 것으로 보인다.