• Archives of Pharmacal Research
• /
• v.28 no.3
• /
• pp.249-268
• /
• 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.

• Korean Journal of Poultry Science
• /
• v.42 no.3
• /
• pp.231-238
• /
• 2015

The present study aimed to investigate the effects of lycopene on hepatic metabolic- and immune-related gene expression in laying hens. A total of 48 25-week-old White Leghorn hens were randomly allocated into four groups consisting of four replicates of three birds: control (basal diet), T1 (basal diet + 10 mg/kg of tomato powder-containing lycopene), T2 (basal diet + 10 mg/kg of micelles of tomato powder-containing lycopene), and T3 (basal diet + 10 mg/kg of purified lycopene). Chickens were fed ad libitum for 5 weeks, and then total RNA was extracted from the livers for quantitative RT-PCR analysis. Peroxisome proliferator-activated receptor ${\gamma}$ (PPAR${\gamma}$) expression was decreased in the liver of chickens after lycopene supplementation (P<0.05). Micellar lycopene supplementation decreased the expression of PPAR${\gamma}$ target genes including fatty acid binding protein 4 (FABP4) and fatty acids synthase (FASN) in the T2 group (P<0.05). Sterol regulatory element-binding protein 2 (SREBP2) and C/EBP-${\alpha}$ were also downregulated in hens fed with micellar lycopene (P<0.05). Glucose transporter 8 (GLUT-8) was upregulated in the T2 and T3 groups (P<0.05). However, the expression of carnitine palmitoyltransferase 1 (CPT-1) was not changed by lycopene supplementation. Pro-inflammatory cytokines such as tumor necrosis factor ${\alpha}$ (TNF-${\alpha}$) and interleukin 6 (IL-6) were downregulated by lycopene supplementation (P<0.05). These data suggest that the type of lycopene supplementation is critical and that micelles of tomato powder-containing lycopene may play an important role in the modulation of lipid metabolism and immunity in chickens.

• Journal of the Korean Society of Food Science and Nutrition
• /
• v.31 no.5
• /
• pp.796-801
• /
• 2002

To investigate the effects of Ewomia ulmoides olivon extract on the serum and hepatic lipid status and anti-oxidant enzyme activities, male Sprague Dawley (SD) rats were given high fat diets and Eucomia ulmoides olivon ethanol extracts for 6 weeks. Rats were divided into (our groups consisting the control (C), Eucomia ulmoides oliuon extract fed group (CE), high fat diet group (CL) and the extract and high fat fed group (CLE). Eucomia ulmoides oliuon ethanol extract lowered total cholesterol, but increased HDL-cholesterol and HDL-cholesterol/total cholesterol of the serum compared to the control. On the other hand, the ratio of HDL-cholesterol/total cho-lcsterol (HTR) was increased by 55% (p<0.05). High fat diet significantly increased serum cholesterol contents, but decreased HDL-cholesterol level and HTR (p<0.05). Atherogenic index (AI) of CL group was increased by almost four times of the control (p<0.05). Triglycerides (TG) and phospholipids were also increased by high fat diet. Eucomia ulmoides oliuon ethanol extract decreased the levels of TG (p<0.05) and phospholipids (p<0.05). Although liver antioxidant engyme activities including glutathione sulfur transferase (GST), superoxide dismutase (SOD) and catalase were decreased by high fat diet, those were stimulated by the administration of Eucommia ulmoides olivon ethanol extract.

• BMB Reports
• /
• v.32 no.3
• /
• pp.232-238
• /
• 1999

Sex differences in the induction of microsomal cytochrome P-450 (CYP) and the activities of several related enzymes of Sprague-Dawley rats treated with 1-bromopropane (1-BrP) were investigated. Male and female rats were exposed to 50, 300, and 1800 ppm of 1-BrP per kg body weight (6 h a day,S days a week, 8 weeks) by inhalation. The mean body weight of 1-BrP treated groups increased according to the day elapsed, but four and five weeks respectively after the start of the exposure, the mean body weight of male and female rats had significantly reduced in the group treated with 1800 ppm 1-BrP compared with the control group (p<0.01). While the relative weights of liver increased in both sexes, statistical significance in both sexes was found only in the group receiving 1800 ppm/kg of 1-BrP (p<0.01). The total contents of CYP, $b_5$, NADPH-P-450 reductase, NADH $b_5$ reductase, ethoxyresorufin-O-deethylase (EROD), pentoxyresorufin-O-dealkylase (PROD), and p-nitrophenol hydroxylase (pNPH) activities were examined for the possible effects of 1-BrP. No significant changes in the CYP and $b_5$ contents, NADPH-P-450 reuctase, NADH $b_5$ reductase, ethoxyresorufin-O-deethylase (EROD), and pentoxyresorufin- O-dealkylase (PROD) were observed between the control and treated groups. The activity of pNPH increased steadily with the increase in the concentration of 1-BrP in both sexes, but was significantly increased only in the 1800 ppm-treated group of male rats (p<0.05). When Western blottings were carried out with three monoclonal antibodies (MAb 1-7-1, MAb 2-66-3, and MAb 1-98-1) which were specific against CYP1A1/2, CYP2B1/2, and CYP2E1, respectively, a strong signal corresponding to CYP2E1 was observed in microsomes obtained from rats treated with 1-BrP. Glutathione S-transferase (GST) activity and the content of lipid peroxide significantly increased in the treated groups compared with the control group (p<0.05). These results suggest that 1-BrP can primarily induce CYP2E1 as the major form and that GST phase II enzymes play important roles in 1-BrP metabolism, showing sex-dependence in the metabolic mechanism of 1-BrP in the rat liver.

• Journal of Food Hygiene and Safety
• /
• v.26 no.3
• /
• pp.235-241
• /
• 2011

Although the vegetable Angelica keiskei (AK) has widely been utilized for the purpose of general health improvement among Korean population, its functionalities are not very well defined. In this study, we examined the effects of methanol extract of AK in rats on the biochemical changes induced by two hepatotoxins, D-galactosamine (GalN) and carbon tetrachloride ($CCl_4$). AK was orally administered once daily for 7 days to male rats at 200 and 500 mg/kg, before hepatotoxins. Effects of AK were assessed 24 hr later. AK pretreatments at 200 and 500 mg/kg significantly blunted GalN-induced elevation in liver lipid peroxidation, plasma aspartate-transaminase (AST) and alanine-transaminase (ALT) activities. AK also prevented, after 500 mg/kg but not after 200 mg/kg, the GalN-induced elevation in triglyceride, total cholesterol and LDL-cholesterol levels. Differently from against GalN-induced toxicity, AK did further elevate the $CCl_4$-induced rise in AST, ALT and lipid peroxidation. These results suggest that AK, when pre-administered prior to GalN, exerted protective effects against GalN-induced hepatotoxicity, in contrast however, AK exacerbated that induced by $CCl_4$. To explore possible mechanism for the toxicity-potentiating effects of AK on $CCl_4$, the activity of hepatic drug metabolism after AK treatment was assessed. It was observed that AK increased the activity of aniline hydroxaylase, a cytochrome P450 isoenzyme responsible for metabolic activation of $CCl_4$. This finding suggests that hepatoprotective effects of AK are not equally expected depending on hepatotoxins employed.

• Toxicological Research
• /
• v.23 no.1
• /
• pp.55-63
• /
• 2007

Diethylnitrosamine (DEN) is a nitrosamine compound that can induce a variety of liver lesions including hepatic carcinoma, forming DNA-carcinogen adducts. In the present study, microarray analyses were performed with Affymetrix Murine Genome 430A Array in order to identify the gene-expression profiles for DEN and to provide valuable information for the evaluation of potential hepatotoxicity. C57BL/6NCrj mice were orally administered once with DEN at doses of 0, 3, 7 and 20 mg/kg. Liver from each animal was removed 2, 4, 8 and 24 hrs after the administration. The histopathological analysis and serum biochemical analysis showed no significant difference in DEN-treated groups compared to control group. Conversely, the principal component analysis (PCA) profiles demonstrated that a specific normal gene expression profile in control groups differed clearly from the expression profiles of DEN-treated groups. Within groups, a little variance was found between individuals. Student's t-test on the results obtained from triplicate hybridizations was performed to identify those genes with statistically significant changes in the expression. Statistical analysis revealed that 11 genes were significantly downregulated and 28 genes were upregulated in all three animals after 2 h treatment at 20 mg/kg. The upregulated group included genes encoding Gdf15, JunD1, and Mdm2, while the genes including Sox6, Shmt2, and SIc6a6 were largely down regulated. Hierarchical clustering of gene expression also allowed the identification of functionally related clusters that encode proteins related to metabolism, and MAPK signaling pathway. Taken together, this study suggests that match with a toxicant signature can assign a putative mechanism of action to the test compound if is established a database containing response patterns to various toxic compounds.

• The Korea Journal of Herbology
• /
• v.25 no.3
• /
• pp.1-9
• /
• 2010

Objectives : This study was undertaken to verify the effects of Gyeongshingangjeehwan18 (GGEx18) on obesity using ob/ob male mice. Methods : Eight-week old mice (wild-type C57BL/6J and ob/ob) were used for all experiments. Wild-type C57BL/6J mice were used as lean control and obese ob/ob mice were randomly divided into 5 groups: obese control, GGEx15, GGEx16, GGEx17, and GGEx18. After mice were treated with several kinds of GGEx for 11 weeks, body weight gain, feeding efficiency ratio, plasma lipid and glucose metabolism. Results : 1. Compared with obese controls, GGEx-treated mice had lower body weight gain and feeding efficiency ratio, the magnitudes of which were prominent in GGEx16 and GGEx18. 2. Consistent with their effects on body weight gain, GGEx16 and GGEx18 not only decreased plasma triglycerides levels, but also increased HDL-cholesterol concentration. 3. CT analysis revealed that visceral fat areas were decreased in all treatment groups compared with obese control mice. The decrease in visceral fat area was prominent in GGEx16 and GGEx18, although they were not statistically significant. 4. The size of adipocytes were significantly decreased by GGEx18, whereas the adipocyte number per unit area was significantly increased, suggesting that GGEx18 decreased the number of large adipocytes. Hepatic lipid accumulation was decreased by GGEx16 and GGEx18, and the inhibitory effect was most effective in GGEx18. 5. Plasma GOT and GPT concentrations were significantly lower following GGEx16 and GGEx18 treatment compared with obese controls. Organ weights were not changed by GGEx treatment, indicating GGEx do not show any toxic effects. Conclusions : These results suggest that GGEx may regulate obesity. Of the 4 compositions, GGEx18 seems to be most effective in improving obesity and lipid disorders.

• Biomolecules & Therapeutics
• /
• v.18 no.4
• /
• pp.469-476
• /
• 2010

This study was to investigate the effect of apigenin on the bioavailability of paclitaxel after oral and intravenous administration in rats. The effect of apigenin on P-glycoprotein (P-gp), cytochrome P450 (CYP)3A4 activity was evaluated. The pharmacokinetic parameters of paclitaxel were determined in rats after oral (40 mg/kg) or intravenous (5 mg/kg) administration of paclitaxel with apigenin (0.4, 2 and 8 mg/kg) to rats. Apigenin inhibited CYP3A4 activity with 50% inhibition concentration ($IC_{50}$) of 1.8 ${\mu}M$. In addition, apigenin significantly inhibited P-gp activity. Compared to the control group, apigenin significantly increased the area under the plasma concentration-time curve (AUC, p<0.05 by 2 mg/kg, 59.0% higher; p<0.01 by 8 mg/kg, 87% higher) of oral paclitaxel. Apigenin also significantly (p<0.05 by 2 mg/kg, 37.2% higher; p<0.01 by 8 mg/kg, 59.3% higher) increased the peak plasma concentration ($C_{max}$) of oral paclitaxel. Apigenin significantly increased the terminal half-life ($t_{1/2}$, p<0.05 by 8 mg/kg, 34.5%) of oral paclitaxel. Consequently, the absolute bioavailability (A.B.) of paclitaxel was significantly (p<0.05 by 2 mg/kg, p<0.01 by 8 mg/kg) increased by apigenin compared to that in the control group, and the relative bioavailability (R.B.) of oral paclitaxel was increased by 1.14- to 1.87-fold. The pharmacokinetics of intravenous paclitaxel were not affected by the concurrent use of apigenin in contrast to the oral administration of paclitaxel. Accordingly, the enhanced oral bioavailability by apigenin may be mainly due to increased intestinal absorption caused via P-gp inhibition by apigenin rather than to reduced renal and hepatic elimination of paclitaxel. The increase in the oral bioavailability might be mainly attributed to enhanced absorption in the gastrointestinal tract via the inhibition of P-gp and reduced first-pass metabolism of paclitaxel via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver by apigenin. It appears that the development of oral paclitaxel preparations as a combination therapy is possible, which will be more convenient than the i.v. dosage form.

• Tuberculosis and Respiratory Diseases
• /
• v.45 no.3
• /
• pp.546-552
• /
• 1998

Background: Up to 90% of a theophylline dose is biotransformed, by interaction with one or more the variants of the cytochrome P-450 drug metabolism system. Macrolides affect the elimination of theophylline by influencing on the microsomal enzyme systems. We evaluate the effect of erythromycin and new macrolides on the serum theophylline level and clearance. Method : Subjects consisted of moderate asthmatic patients with normal renal and hepatic functions. All subjects were non-smokers and treated with oral theophylline 400 mg per day. We randomly assigned 53 patients into four groups. Each group was treated with one macrolides, the first group erythromycin(n:19, 500 mg bid), second roxithromycin (n:14. 150 mg bid), third clarithromycin (n:10, 250 mg bid) and fourth azithromycin(n:10, 250 mg bid). We measured the serum theophylline level and clearance at three intervals, at pretreatment, after the first and fourth week after receiving the following macrolides, erythromycin, roxithromycin and clarithromycin. When azithromycin was administered, the serum theophylline level was measured at pretreatment and after one week of treatment They were measured by a computerized program of Bayesian method. Results : When compared with control, erythromycin and roxithromycin-treated groups had a significantly elevated serum theophylline level and decreased clearance. However, there were no significant changes of the serum theophylline level and clearance in clarithromycin and azithromycin-treated groups. Conclusion : These results suggest that theophylline dose may need to be readjusted and have periodic drug monitoring when erythromycin or roxithromycin is administered concurrently.

• Korean Journal of Poultry Science
• /
• v.13 no.1
• /
• pp.31-40
• /
• 1986

The energy metabolism with the normal laying hen and progesterone injected non-laying hen are compared. 1. The FHP of 109.7Kcal for laying hen was 25.5 percent higher than the 87.4 Kcal found for non-laying hen. 2. The MEm's of laying hen and non-laying hen were 149, and 135Kcal/Kg$\^$0.75/day and NAME's of the diets were 77 and 83 percent, respectively. For the laying hen shown negative retention in body energy during the experiment, the 77 percent NAME was the value of supporting egg production. For the non-laying hen shown the positive retention in body energy and zero egg production, the 83 percent NAME was of growth. 3. A change in body weight of 1g was comparable to 3.54 Kcal for laying hen, and 5.0 Kcal for non-laying hen, when calculated on regression equations between body weight change and body energy retention(BE). The figures indicate that the tissue energy is used with an efficiency of 70 percent for egg production. 4. Plasma level of triiodothyronine(T3) for the laying hen is appeared to be higher than that of non-laying hen, although the levels of thyroxine (T4) are equal both in laying and non-laying hen. 5. Activities of four hepatic enzymes(ATP citrate lyase, fructose diphosphate aldolase, isocitrate dehydrogenase and glutamte pyruvic transaminase) were significantly greater in the laying hen than in the non-laying hen.