• 제목/요약/키워드: CYP3A5

검색결과 214건 처리시간 0.019초

In Vitro Metabolism of a New Cardioprotective Agent, KR-33028 in the Human Liver Microsomes and Cryopreserved Human Hepatocytes

  • Kim Hyojin;Yoon Yune-Jung;Kim Hyunmi;Cha Eun-Young;Lee Hye Suk;Kim Jeong-Han;Yi Kyu Yang;Lee Sunkyung;Cheon Hyae Gyeong;Yoo Sung-Eun;Lee Sang-Seop;Shin Jae-Gook;Liu Kwang-Hyeon
    • Archives of Pharmacal Research
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    • 제28권11호
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    • pp.1287-1292
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    • 2005
  • KR-33028 (N-[4-cyano-benzo[b]thiophene-2-carbonyl]guanidine) is a new cardioprotective agent for preventing ischemia-reperfusion injury. This study was performed to identify the metabolic pathway of KR-33028 in human liver microsomes and to compare its metabolism with that of cryopreserved human hepatocytes. Human liver microsomal incubation of KR-33028 in the presence of NADPH and UDPGA resulted in the formation of four metabolites, M1, M2, M3, and M4. M1 and M2 were identified as 5-hydroxy-KR-33028 and 7-hydroxy-KR-33028, respectively, on the basis of LC/MS/MS analysis with the synthesized authentic standard. M3 and M4 were suggested to be dihydroxy-KR-33028 and hydroxy-KR-33028-glucuronide, respectively. Metabolism of KR-33028 in cryopreserved human hepatocytes resulted in the formation of M1, M2, and M4. These data show a good correlation between major metabolites formed in human liver microsomes and cryopreserved human hepatocytes. In addition, KR­33028 was found to inhibit moderately the metabolism of CYP1A2 substrates. Based on the results obtained metabolic pathway of KR-33028 is proposed.

사염화 탄소에 의한 간손상에 있어 Kupffer cell 칼슘의 역할 (Involvement of Kupffer Cell in $CCl_4$ induced Liver Injury: The Role of Calcium)

  • 양미라
    • 대한약리학회지
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    • 제32권1호
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    • pp.75-82
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    • 1996
  • 사염화 탄소에 의한 과산화 지질 증가 및 간 손상에 calcium 및 Kupffer cell의 역할 및 calcium channel blocker의 간 손상에 대한 방어 효과를 연구하였다. 사염화 탄소는 (1 gm/kg, ig) 간의 malondialdehyde (nmole/gm liver) 및 혈중 AST와 ALT (lU/ml) 활성도의 현저한 증가를 나타내었다. 고 농도의 Retinol (250,000U/kg/day)로 인한 Kupffer cell의 활성 증가는 사염화 탄소에 의한 간 과산화 지질 증가 및 간 손상에 상승 작용을 나타낸 반면, $GdCl_3$ 전처리는 $CCl_4$로 인한 ALT의 증가를 감소시켰다. 한편 Retinol 처치군에 Diltiazem (10mg/kg/day)을 병행하여 처치한 결과, 사염화 탄소에 의한 혈중 AST 및 ALT의 증가를 Retinol 단독 처치군에 비하여 현저하게 억제시킬 수 있었다. 이 결과들이 Retinol 혹은 Diltiazem의 투여에 의한 사염화 탄소가 cytochrome P450에 의한 대사 활성 또는 GSH와 관련된 항산화 기전에 미치는 영향에 기인한 것인가를 규명하기 위하여 cytochrome P450, cytochrome P4502El 활성도, GSH reductase 및 GSH peroxidase 활성도를 측정하였다. 그 결과, Retinol 및 Diltiazem의 전처리는 이들 효소의 활성도에 미치는 영향은 대조군에 비하여 유의한 차이가 없었다. 이상의 실험 결과를 종합하여 보면, 사염화 탄소의 투여에 의한 간 손상은 세포내 calcium의 증가를 가져오며, 이는 이차적으로 Kupffer cell을 활성화 시켜 이미 손상된 간세포의 독성을 증가시켰으며, calcium channel blocker인 Diltiazem의 투여는 사염화 탄소의 간독성을 현저하게 감소시키는 효과를 나타내었다.

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Glutathione S-Transferase 유전적 다형성이 항산화 체계에 미치는 영향 (Effect of Glutathione S-Transferase Polymorphisms on the Antioxidant System)

  • 전경임;박은주
    • 한국식품영양과학회지
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    • 제36권6호
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    • pp.708-719
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    • 2007
  • 본 연구에서는 104명의 성인남녀를 대상으로 그들의 GSTT1, GSTM1, GSTP1의 유전적 다형성 분포도를 조사한 결과, 전체 대상자들 중 각각 60명(57.4%), 42명(40.6%)가 GSTT1 과 GSTM1의 유전자를 가지고 있었으며, GSTT1과 GSTM1 유전자가 둘 다를 가진 대상자는 27명(25.7%), 둘 중에 하나만 가지고 있는 사람은 47명(45.5%) 그리고 둘 다 없는 사람은 30명으로 28.7%에 해당되었다. GSTP1 유전자의 경우 homozygous(a/a) wild type은 79명(75.5%)으로 대부분의 대상자가 여기에 해당되었으며, heterozygous(a/b) heterozygous type은 22명(21.6%), 그리고 homozygous(b/b) wild type으로 나타난 대상자는 3명(2.9%)이었다. GSTT1 null type은 산화적 스트레스를 더 많이 받고 있는 것으로 알려진흡연자의 비율이 present 군에 비해 낮음에도 불구하고 적혈구 GSH의 농도는 유의적으로 낮고 임파구 DNA 손상정도는 유의적으로 높은 것으로 나타났다. GSTM1 유전자의 경우 적혈구 GSH-Px의 활성만이 GSTM1 null type이 presenttype에 비해 유의적으로 높은 것으로 나타났으며, 나머지 다른 지표에서는 GSTM1 null type과 present type 간의 유의적인 차이가 없었다. GSTP1 유전자 다형성에 따른 항산화 영양상태의 유의적인 차이는 없었다. 흡연과 GST 유전자 다형성의 상호작용결과, 혈장 ${\alpha}$-carotene 농도, 적혈구 GSH-Px와 GST 활성은 GSTT1 null type의 경우 흡연자에 비해 비흡연자가 유의적으로 높게 나타났으며, GSTT1 present type에서는 흡연자와 비흡연자간의 유의적인 차이가 없는 것으로 나타났다. GSTM1 유전자의 경우 GSTM1의 null type에서 흡연자의 경우 비흡연자에 비해 혈장 ${\gamma}$-tocopherol과 ${\beta}$-carotene 수준이 유의적으로 낮았다. GSTT1과 GSTM1 유전자가 둘 다 없는 경우(both null)에는 흡연자의 혈장 lycopene과 적혈구 GST 활성이 비흡연자에 비해 유의적으로 낮았다. GSTP1 유전자의 경우 혈장 ${\alpha}$-carotene과 적혈구 GSH-Px 활성은 a/a type의 흡연자가 비흡연자에 비해 유의적으로 낮았고, 적혈구 catalase의 활성은 a/b type에서 흡연자가 비흡연자에 비해 유의적으로 낮았으며, ${\beta}$-carotene 농도는 두 type 모두에서 유의적으로 흡연자가 낮았다. 이상의 연구 결과 GST 유전적 다형성에따라 산화, 항산화 관련 효소 활성 및 항산화 영양소 수준의상태가 차이가 있음을 알 수 있었으며, 특히 흡연자의 경우 GST 유전자 type에 따라 항산화 영양상태가 더 큰 영향을 받음을 알 수 있었다. 이러한 연구 결과는 유전적 다형성에따라 항산화 영양소의 권장수준을 책정하는데 기초연구자료로 활용될 수 있을 것이다. 즉, GSTT1 또는 GSTM1 null type의 경우 비흡연자에 비해 흡연자가 항산화 영양소 수준이 더 낮게 나타났으므로 그들의 체내 항산화 영양 상태를 증가시킬 수 있는 여러 방안들, 즉 항산화 비타민의 보충투여 및 야채와 과일의 섭취 권장 등이 고려될 수 있을 것이다. 또한 GST 유전자 다형성에 따라 항산화 영양상태의 차이가 있으므로 항산화 관련 in vitro 실험, 동물 및 인체 실험의 결과 해석 시 나타나는 개인 간의 변이차이는 GST 유전자 다형성으로 일부분 설명될 수 있으리라 기대된다. 향후대상자의 범위를 좀 더 넓혀서 GST 유전자 다형성과 항산화 영양상태의 관계를 규명하고자 하며 더불어 산화물질 해독에 관여하는 다른 유전자(CYP 450, SULT 등)의 역할에 대해서도 계속적인 연구가 필요하다고 사료된다.

한국가족계획사업(韓國家族計劃事業)의 문제점(問題點) (Problems in the Korean National Family Planning Program)

  • 홍종관
    • Clinical and Experimental Reproductive Medicine
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    • 제2권2호
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    • pp.27-36
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    • 1975
  • The success of the family planning program in Korea is reflected in the decrease in the growth rate from 3.0% in 1962 to 2.0% in 1971, and in the decrease in the fertility rate from 43/1,000 in 1960 to 29/1,000 in 1970. However, it would be erroneous to attribute these reductions entirely to the family planning program. Other socio-economic factors, such as the increasing age at marriage and the increasing use of induced abortions, definitely had an impact on the lowered growth and fertility rate. Despite the relative success of the program to data in meeting its goals, there is no room for complacency. Meeting the goal of a further reduction in the population growth rate to 1.3% by 1981 is a much more difficult task than any one faced in the past. Not only must fertility be lowered further, but the size of the target population itself will expand tremendously in the late seventies; due to the post-war baby boom of the 1950's reaching reproductive ages. Furthermore, it is doubtful that the age at marriage will continue to rise as in the past or that the incidence of induced abortion will continue to increase. Consequently, future reductions in fertility will be more dependent on the performance of the national family planning program, with less assistance from these non-program factors. This paper will describe various approaches to help to the solution of these current problems. 1. PRACTICE RATE IN FAMILY PLANNING In 1973, the attitude (approval) and knowledge rates were quite high; 94% and 98% respectively. But a large gap exists between that and the actual practice rate, which is only 3695. Two factors must be considered in attempting to close the KAP-gap. The first is to change social norms, which still favor a larger family, increasing the practice rate cannot be done very quickly. The second point to consider is that the family planning program has not yet reached all the eligible women. A 1973 study determineded that a large portion, 3096 in fact, of all eligible women do not want more children, but are not practicing family planning. Thus, future efforts to help close the KAP-gap must focus attention and services on this important large group of potential acceptors. 2. CONTINUATION RATES Dissatisfaction with the loop and pill has resulted in high discontinuation rates. For example, a 1973 survey revealed that within the first six months initial loop acceptance. nearly 50% were dropouts, and that within the first four months of inital pill acceptance. nearly 50% were dropouts. These discontinuation rates have risen over the past few years. The high rate of discontinuance obviously decreases the contraceptive effectiveness. and has resulted in many unwanted births which is directly related to the increase of induced abortions. In the future, the family planning program must emphasize the improved quality of initial and follow-up services. rather than more quantity, in order to insure higher continuation rates and thus more effective contraceptive protection. 3. INDUCED ABORTION As noted earlier. the use of induced abortions has been increase yearly. For example, in 1960, the average number of abortions was 0.6 abortions per women in the 15-44 age range. By 1970. that had increased to 2 abortions per women. In 1966. 13% of all women between 15-44 had experienced at least one abortion. By 1971, that figure jumped to 28%. In 1973 alone, the total number of abortions was 400,000. Besides the ever incre.sing number of induced abortions, another change has that those who use abortions have shifted since 1965 to include- not. only the middle class, but also rural and low-income women. In the future. in response to the demand for abortion services among rural and low-income w~men, the government must provide and support abortion services for these women as a part of the national family planning program. 4. TARGET SYSTIi:M Since 1962, the nationwide target system has been used to set a target for each method, and the target number of acceptors is then apportioned out to various sub-areas according to the number of eligible couples in each area. Because these targets are set without consideration for demographic factors, particular tastes, prejudices, and previous patterns of acceptance in the area, a high discontinuation rate for all methods and a high wastage rate for the oral pill and condom results. In the future. to alleviate these problems of the methodbased target system. an alternative. such as the weighted-credit system, should be adopted on a nation wide basis. In this system. each contraceptive method is. assigned a specific number of points based upon the couple-years of protection (CYP) provided by the method. and no specific targets for each method are given. 5. INCREASE OF STERILIZA.TION TARGET Two special projects. the hospital-based family planning program and the armed forces program, has greatly contributed to the increasing acceptance in female and male sterilization respectively. From January-September 1974, 28,773 sterilizations were performed. During the same time in 1975, 46,894 were performed; a 63% increase. If this trend continues, by the end of 1975. approximately 70,000 sterilizations will have been performed. Sterilization is a much better method than both the loop and pill, in terms of more effective contraceptive protection and the almost zero dropout rate. In the future, the. family planning program should continue to stress the special programs which make more sterilizations possible. In particular, it should seek to add the laparoscope techniques to facilitate female sterilization acceptance rates. 6. INCREASE NUMBER OF PRIVATE ACCEPTORS Among the current family planning users, approximately 1/3 are in the private sector and thus do not- require government subsidy. The number of private acceptors increases with increasing urbanization and economic growth. To speed this process, the government initiated the special hospital based family planning program which is utilized mostly by the private sector. However, in the future, to further hasten the increase of private acceptors, the government should encourage doctors in private practice to provide family planning services, and provide the contraceptive supplies. This way, those do utilize the private medical system will also be able to receive family planning services and pay for it. Another means of increasing the number of private acceptors, IS to greatly expand the commercial outlets for pills and condoms beyond the existing service points of drugstores, hospitals, and health centers. 7. IE&C PROGRAM The current preferred family size is nearly twice as high as needed to achieve a stable poplation. Also, a strong boy preference hinders a small family size as nearly all couples fuel they must have at least one or more sons. The IE&C program must, in the future, strive to emphasize the values of the small family and equality of the sexes. A second problem for the IE&C program to work. with in the: future is the large group of people who approves family planning, want no more children, but do not practice. The IE&C program must work to motivate these people to accept family planning And finally, for those who already practice, an IE&C program in the future must stress continuation of use. The IE&C campaign, to insure highest effectiveness, should be based on a detailed factor analysis of contraceptive discontinuance. In conclusion, Korea faces a serious unfavorable sociodemographic situation- in the future unless the population growth rate can be curtailed. And in the future, the decrease in fertility will depend solely on the family planning program, as the effect of other socio-economic factors has already been maximumally felt. A second serious factor to consider is the increasing number of eligible women due to the 1950's baby boom. Thus, to meet these challenges, the program target must be increased and the program must improve the effectiveness of its current activities and develop new programs.

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