• Archives of Pharmacal Research
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• 제28권3호
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• pp.249-268
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• 2005

Drug metabolizing enzymes (DMEs) play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. Most of the tissues and organs in our body are well equipped with diverse and various DMEs including phase I, phase II metabolizing enzymes and phase III transporters, which are present in abundance either at the basal unstimulated level, and/or are inducible at elevated level after exposure to xenobiotics. Recently, many important advances have been made in the mechanisms that regulate the expression of these drug metabolism genes. Various nuclear receptors including the aryl hydrocarbon receptor (AhR), orphan nuclear receptors, and nuclear factor-erythoroid 2 p45-related factor 2 (Nrf2) have been shown to be the key mediators of drug-induced changes in phase I, phase II metabolizing enzymes as well as phase III transporters involved in efflux mechanisms. For instance, the expression of CYP1 genes can be induced by AhR, which dimerizes with the AhR nuclear translocator (Arnt) , in response to many polycyclic aromatic hydrocarbon (PAHs). Similarly, the steroid family of orphan nuclear receptors, the constitutive androstane receptor (CAR) and pregnane X receptor (PXR), both heterodimerize with the ret-inoid X receptor (RXR), are shown to transcriptionally activate the promoters of CYP2B and CYP3A gene expression by xenobiotics such as phenobarbital-like compounds (CAR) and dexamethasone and rifampin-type of agents (PXR). The peroxisome proliferator activated receptor (PPAR), which is one of the first characterized members of the nuclear hormone receptor, also dimerizes with RXR and has been shown to be activated by lipid lowering agent fib rate-type of compounds leading to transcriptional activation of the promoters on CYP4A gene. CYP7A was recognized as the first target gene of the liver X receptor (LXR), in which the elimination of cholesterol depends on CYP7A. Farnesoid X receptor (FXR) was identified as a bile acid receptor, and its activation results in the inhibition of hepatic acid biosynthesis and increased transport of bile acids from intestinal lumen to the liver, and CYP7A is one of its target genes. The transcriptional activation by these receptors upon binding to the promoters located at the 5-flanking region of these GYP genes generally leads to the induction of their mRNA gene expression. The physiological and the pharmacological implications of common partner of RXR for CAR, PXR, PPAR, LXR and FXR receptors largely remain unknown and are under intense investigations. For the phase II DMEs, phase II gene inducers such as the phenolic compounds butylated hydroxyanisol (BHA), tert-butylhydroquinone (tBHQ), green tea polyphenol (GTP), (-)-epigallocatechin-3-gallate (EGCG) and the isothiocyanates (PEITC, sul­foraphane) generally appear to be electrophiles. They generally possess electrophilic-medi­ated stress response, resulting in the activation of bZIP transcription factors Nrf2 which dimerizes with Mafs and binds to the antioxidant/electrophile response element (ARE/EpRE) promoter, which is located in many phase II DMEs as well as many cellular defensive enzymes such as heme oxygenase-1 (HO-1), with the subsequent induction of the expression of these genes. Phase III transporters, for example, P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), and organic anion transporting polypeptide 2 (OATP2) are expressed in many tissues such as the liver, intestine, kidney, and brain, and play crucial roles in drug absorption, distribution, and excretion. The orphan nuclear receptors PXR and GAR have been shown to be involved in the regulation of these transporters. Along with phase I and phase II enzyme induction, pretreatment with several kinds of inducers has been shown to alter the expression of phase III transporters, and alter the excretion of xenobiotics, which implies that phase III transporters may also be similarly regulated in a coordinated fashion, and provides an important mean to protect the body from xenobiotics insults. It appears that in general, exposure to phase I, phase II and phase III gene inducers may trigger cellular 'stress' response leading to the increase in their gene expression, which ultimately enhance the elimination and clearance of these xenobiotics and/or other 'cellular stresses' including harmful reactive intermediates such as reactive oxygen species (ROS), so that the body will remove the 'stress' expeditiously. Consequently, this homeostatic response of the body plays a central role in the protection of the body against 'environmental' insults such as those elicited by exposure to xenobiotics.

• 한국토양비료학회지
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• 제39권5호
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• pp.259-267
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• 2006

수리 전도도는 수리구배에 대한 플럭스의 비율을 나타내며, 포화된 토양에서의 물의 이동이 포화수리전도도이고 불포화된 토양에서의 이동이 불포화수리전도도이다. 일반적인 밭 상태에서의 토양수분 조건은 불포화수리전도도로 표시하는 것이 적절하나 그 상태를 표현하기가 쉽지 않다. 토양의 불포화 상태를 나타내는데 가장 많이 쓰이고 있는 VGM(van Genuchten Mualem) 모형은 토양수분 포텐셜과 수분함량의 함수로 구성된 모형이며 몇 가지 매개변수가 필요하다. VGM 모형의 매개변수를 얻기 위해 본 연구에서는 VGM 모형의 매개변수를 계산해주는 프로그램인 Rosetta를 사용하였다. Rosetta 모형은 신경그물 얼개(neural network)를 이용하여 토양의 물리적 자료들인 토성이나 모래, 미사, 점토 함량 또는 용적밀도나 33 kPa, 1500 kPa에서의 토양수분 함량 자료를 가지고 VGM의 매개변수인 Ko(effedive saturated hydraulic conductivity), ${\theta}r$(residual soil water content), ${\theta}s$(saturated soil water content), L, n, m(=1-1/n)을 예측하는 모형으로 미국 농무성(USDA-ARS)에서 개발한 프로그램이다. Rosetta를 이용하여 10kPa에서의 불포화수리전도도를 예측하였다. 또한 Gardner와 Wooding의 모형을 기반으로 하여 만들어진 장력침투계의 포화수리전도도 값을 Gardner식에 적용하여 1, 3, 5, 7 kPa에서의 불포화수리전도도 값을 17개 토양통을 대상으로 하여 구했다. 토양수분 potential이 3 kPa에서는 물의 이동이 거의 없는 토양들이 있었는데 반해 남계통을 비롯한 학곡통, 회곡통, 백산통, 상주통, 석천통, 예산통 등 7개의 토양은 3 kPa에서도 약간의 물의 이동이 있었다. 또한, 1 kPa에서 물의 이동은 삼각통에서 $40.8{\times}10^{-5}cm{\cdot}sec^{-1}$로 이동 속도가 가장 컸으며 그 뒤로 예산통, 화봉통, 학곡통, 백산통 등이 토양에서 빠른 속도로 이동하였다. 가천통이나 석천통 및 우곡통은 1 kPa에서의 이동 속도가 아주 느린 토양으로 판단되었다. PTF와 VG모형에 의해 얻어진 10 kPa에서의 수분함량 예측 값을 VGM 모형에 적용해 불포화수리전도도를 구했을 때, VG모형에 의한 예측 값은 존재하는 반면 PTF에 의한 값은 결측 값이 존재해 그 적용에 한계가 있었다. 그리고 1 kPa에서 불포화 수리전도도를 VGM 모형으로 예측한 값과 측정된 값을 Gardner 모형으로 해석한 값을 비교했을 때 자갈이 없는 토양에서는 일정한 경향(exponential 함수)이 존재한 반면, 자갈이 있는 토양에서는 경향을 발견할 수가 없었다. 이상의 결과로 불포화 수리전도도 특성평가에 대한 VGM 모형의 적용성을 살펴보았을 때는 우리나라와 같이 경사지가 많고 토심이 깊지 않으면서 자갈함량이 많은 토양에서는 한계가 있을 것으로 판단되었다.