• 한국임상약학회지
• /
• 제30권1호
• /
• pp.31-35
• /
• 2020

Objective: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are frequently prescribed medications worldwide for the treatment of hypercholesterolemia. Statins are considered to be well tolerated; however, they have a potential for myotoxicity. Concomitant drugs that inhibit cytochrome P450 3A4 can increase the concentration of statins and thus the risk of developing myotoxicity. The purpose of this study was to evaluate risk factors associated with potential drug-drug interactions in patients receiving statins. Methods: The subjects of this study were patients aged more than 18 years who received at least one prescription of statins in a general hospital located in Chuncheon-si, Korea, between January 1, 2018, and March 31, 2018. Data regarding statin use and baseline characteristics was collected from the computerized hospital database. Logistic regression analysis was used to identify risk factors associated with potential drug-drug interactions. Results: A total of 1061 patients were finally included in the study. The incidence of potential drug-drug interactions was 45% in all subjects. According to the results of the multivariate logistic regression analysis, myocardial infarction as the indication of statin, arrhythmia or heart failure as a comorbidity, and aspartate aminotransferase levels higher than 40 IU/L were significant risk factors for potential drug-drug interactions in study subjects. Diltiazem was the most commonly co-prescribed drug that caused potential drug-drug interactions with statins. Conclusion: There was a considerable rate of potential drug-drug interactions in patients receiving statins. Health care professionals should attempt to reduce potential drug-drug interactions during statin administration.

• 한국식품영양과학회지
• /
• 제37권3호
• /
• pp.294-301
• /
• 2008

본 연구는 삼백초(aururus chinensis), 포공영(Taraxacum platycarpum), 유근피(Ulmus macrocarpa), 감초(Glycyrrhiza glabra), 흑두(Rhynchosia nulubilis)로부터 제조된 생약재 추출 혼합물이 dioxin 중 중독성이 가장 강하다고 알려진 2,3,7,8-tetrachlorodinenzo-p-dioxin(TCDD)에 의한 산화적 스트레스에 미치는 효과를 실험하였다. 정상적인 간세포주를 TCDD에 노출시킨 후 OHEM을 처리한 결과, TCDD에 의한 세포독성을 감소시켰으며, 간세포주로부터 생성된 lactate dehydrogenase, nitric oxide, cytochrome p450의 생성량 측정 결과로 OHEM이 TCDD로 유발된 간 독성을 해독할 수 있는 것으로 나타났다. 그리고 rat을 이용한 TCDD 급성독성 유발 실험에서는 TCDD 투여에 의해 증가된 AST, ALT, ALP, LDH 및 동맥경화지수가 OHEM의 투여에 의해 유의성 있게 감소하였으며 OHEM의 사전투여에 의한 방어효과가 높은 것으로 측정되었다(p<0.05). 또한 OHEM의 투여가 TCDD에 의해 손상된 간세포 조직의 풍선 병변과 공포화를 감소시켰고, 소장 세포의 조직에서는 융모 조직의 부종을 현저하게 감소시켰다.

• Asian-Australasian Journal of Animal Sciences
• /
• 제31권1호
• /
• pp.138-148
• /
• 2018

Objective: Fusarium mycotoxins deoxynivalenol (DON) and zearalenone (ZEN), common contaminants in the feed of farm animals, cause immune function impairment and organ inflammation. Consequently, the main objective of this study was to elucidate DON and ZEN effects on the mRNA expression of pro-inflammatory cytokines and other immune related genes in the kidneys of piglets. Methods: Fifteen 6-week-old piglets were randomly assigned to three dietary treatments for 4 weeks: control diet, and diets contaminated with either 8 mg DON/kg feed or 0.8 mg ZEN/kg feed. Kidney samples were collected after treatment, and RNA-seq was used to investigate the effects on immune-related genes and gene networks. Results: A total of 186 differentially expressed genes (DEGs) were screened (120 upregulated and 66 downregulated). Gene ontology analysis revealed that the immune response, and cellular and metabolic processes were significantly controlled by these DEGs. The inflammatory stimulation might be an effect of the following enriched Kyoto encyclopedia of genes and genomes pathway analysis found related to immune and disease responses: cytokine-cytokine receptor interaction, chemokine signaling pathway, toll-like receptor signaling pathway, systemic lupus erythematosus (SLE), tuberculosis, Epstein-Barr virus infection, and chemical carcinogenesis. The effects of DON and ZEN on genome-wide expression were assessed, and it was found that the DEGs associated with inflammatory cytokines (interleukin 10 receptor, beta, chemokine [C-X-C motif] ligand 9, CXCL10, chemokine [C-C motif] ligand 4), proliferation (insulin like growth factor binding protein 4, IgG heavy chain, receptor-type tyrosine-protein phosphatase C, cytochrome P450 1A1, ATP-binding cassette sub-family 8), and other immune response networks (lysozyme, complement component 4 binding protein alpha, oligoadenylate synthetase 2, signaling lymphocytic activation molecule-9, ${\alpha}$-aminoadipic semialdehyde dehydrogenase, Ig lambda chain c region, pyruvate dehydrogenase kinase, isozyme 4, carboxylesterase 1), were suppressed by DON and ZEN. Conclusion: In summary, our results indicate that high concentrations of DON and ZEN suppress the inflammatory response in kidneys, leading to potential effects on immune homeostasis.

• 한국식품영양과학회지
• /
• 제36권4호
• /
• pp.411-418
• /
• 2007

솔잎 열수추출물이 카드뮴으로 유도한 흰쥐의 산화적 손상에 미치는 영향을 살펴보고자 체중 kg당 5mg의 카드뮴$(CdCl_2)$을 매주 1회 경구투여하였다. 솔잎은 매일 일정시각에 체중 kg당 1.26g수준이 되도록 4주간 경구투여 사육한 결과 카드뮴과 솔잎 열수추출은 체중에는 영향을 미치지 않았으며 솔잎 열수추출물은 식이섭취량을 감소시켰다. 체중 100g당 간조직 무게는 카드뮴 대조군이 정상군에 비하여 유의적으로 증가하였으며 솔잎 열수추출물은 간조직 무게를 감소시키는 경향이었다 혈장 중의 AST와 ALT활성은 카드뮴 투여에 의해 유의적으로 증가되었으나 솔잎 열수추출물에 의해 ALT활성이 카드뮴 대조군에 비하여 유의적으로 감소되었다. 혈장 알부민 함량은 실험군간의 차이가 없었으나 크레아티닌 함량은 솔잎 열수추출물 급여시 낮았다. 카드뮴 투여시 간조직의 CYP함량은 유의적으로 감소되었으며 솔잎 열수추출물에 의한 영향은 없었다. 한편 XO와 ADH활성은 솔잎 열수추출물군이 정상군과 카드뮴 대조군에 비하여 유의적으로 높았다. 또한 카드뮴 투여에 인해 유의적으로 높아진 SOD, MAO, CAT 및 GSH-Px 활성도는 솔잎 열수추출물에 의해 정상수준으로 회복되었다. 간조직 중의 글루타티온 함량은 솔잎 열수추출물 급여에 의한 차이가 발견되지 않았으나 MDA함량은 솔잎 열수추출물 급여군에서 카드뮴 대조군에 비하여 유의적인 감소를 보임으로써 카드뮴에 의해 유도된 지질과산화가 솔잎 열수추출물 급여로 개선될 수 있음을 제시한다.

• 대한수의학회지
• /
• 제60권4호
• /
• pp.215-223
• /
• 2020

Sasa (S.) quelpaertensis Nakai (Korean name, Jeju-Joritdae), which has anti-oxidative and anti-inflammatory activities, is a type of bamboo grass distributed widely in Jeju Island, Korea. S. quelpaertensis leaves are used for therapeutic purposes in traditional Korean medicine. This study examined the hepatoprotective effects of the S. quelpaertensis ethyl acetate fraction (SQEA) in a mouse model to mimic alcoholic liver damage. The mice were administered orally with 30% alcohol (5 g/kg) once per day with or without SQEA treatments (100 and 200 mg/kg) for 14 days consecutively. Alcohol consumption increased the serum alcohol content and histopathological changes but reduced the liver weight. Moreover, the livers of the alcohol group exhibited the accumulation of malondialdehyde and cytochrome P450 2E1 (CYP2E1), and lipid droplet coating protein perilipin-2. On the other hand, SQEA dose-dependently attenuated the alcohol-induced serum ethanol content and liver histopathological changes but increased the liver weight. Moreover, SQEA attenuated the level of CYP2E1 and inhibited alcohol-induced lipogenesis in the liver via decreased perilipin-2 expression. These results suggest that SQEA can provide a potent way to reduce the liver damage caused by alcohol consumption.

• The Korean Journal of Physiology and Pharmacology
• /
• 제17권6호
• /
• pp.479-484
• /
• 2013

Given the CYP3A4 and CYP3A5's impact on the efficacy of drugs, the genetic backgrounds of individuals and populations are regarded as an important factor to be considered in the prescription of personalized medicine. However, genetic studies with Korean population are relatively scarce compared to those with other populations. In this study, we aimed to identify CYP3A4/5 polymorphisms and compare the genotype distributions among five ethnicities. To identify CYP3A4/5 SNPs, we first performed direct sequencing with 288 DNA samples which consisted of 96 Koreans, 48 European-Americans, 48 African-Americans, 48 Han Chinese, and 48 Japanese. The direct sequencing identified 15 novel SNPs, as well as 42 known polymorphisms. We defined the genotype distributions, and compared the allele frequencies among five ethnicities. The results showed that minor allele frequencies of Korean population were similar with those of the Japanese and Han Chinese populations, whereas there were distinct differences from European-Americans or African-Americans. Among the pharmacogenetic markers, frequencies of $CYP3A4^*1B$ (rs2740574) and $CYP3A5^*3C$ (rs776742) in Asian groups were different from those in other populations. In addition, minor allele frequency of $CYP3A4^*18$ (rs28371759) was the highest in Korean population. Additional in silico analysis predicted that two novel non-synonymous SNPs in CYP3A5 (+27256C>T, P389S and +31546T>G, I488S) could alter protein structure. The frequency distributions of the identified polymorphisms in the present study may contribute to the expansion of pharmacogenetic knowledge.

• 대한약리학회지
• /
• 제18권1호
• /
• pp.55-63
• /
• 1982

Lipid peroxidation is the reaction of oxidative deterioration of polyunsaturated lipids and this peroxidation involves the direct reaction of oxygen and lipid to form free radical intermediates, which can lead to autocatalysis. As results of the extensive studies on the lipid peroxidation by many authors, the relationship between lipid peroxidation and the drug metabolizing system as well as the actions of free radicals on the peroxidation was reasonably well known. For a long time, the mechanism of hepatotoxicity of $CCl_4$ was not clearly understood. However, it is now quite well established that $CCl_4$ is activated in vivo to a free radical which is a highly reactive molecule. Therefore, lipid peroxidation which induces the reduction of cytochrome P-450 and aminopyrine demethylase activity is known as decisive event of $CCl_4$ hepatotoxicity. On the other hand, it was also reported that singlet molecular oxygen produces lipid peroxidation in liver microsomes. In this study the effects of benzoyl peroxide on the lipid peroxidation and drug-metabolizing enzyme were examined. Benzoyl peroxide mixed with starch and phosphates etc. is usually used as a food additive for flour bleaching and maturing purpose because of its oxidative property. Albino rats were used for the experimental animals. Benzoyl peroxide was suspended in soybean oil and sesame oil and administered intraperitoneally or orally. TBA value and aminopyrine demethylase activity were determined in liver microsomal fraction and serum. The results were summerized as following. 1) Body weights of animals administered benzoyl peroxide suspension were decreased while that of oil administered group were increased. 2) The activity of aminopyrine demethylase was generally decreased in animals administered oil suspension of benzoyl peroxide. Furthermore, the marked reduction of the enzyme activity was observed in animals administered benzoyl peroxide intraperitoneally. 3) Generally, microsomal TBA values as well as serum TBA were significantly elevated in benzoyl peroxide group in comparison with the control group. However, the more remarkable increase of serum TBA than microsomal TBA was observed in animals administered orally for 6 days. 4) Specifically, the changing pattern of TBA value was notable in serum rather than in liver microsome by intraperitoneal administration of benzoyl peroxide.

• KSBB Journal
• /
• 제29권1호
• /
• pp.58-66
• /
• 2014

Demand for in vitro pharmacological evaluation and toxicity test using human hepatocytes has been increasing. In USA and Europe, human hepatocytes obtained from donated whole liver unsuitable for transplantation were distributed to researchers and deposited in cell bank facility as cryopreserved vial. In Korea, however, incidence of transplantation- inappropriate whole liver has been quite low and the whole livers almost have so severe liver disease such as fatty or fibrotic liver that cannot meet the demand. In this study we aimed to isolate human hepatocytes from liver resection surgery-originated partial liver, and assure the isolated human hepatocytes and its cryopreserved hepatocytes to be qualified for the in vitro pharmacological evaluation and drug toxicity tests. We compared those with commercially available human hepatocyte, BD $GenTest^{TM}$ by cell morphology, hepatic gene expression, urea synthesis, albumin secretion, ammonia removal, and cytochrome P450 induction activities. Changes in hepatotoxic gene expression after cryopreservation are evaluated with a typical hepatotoxic drug, acetaminophen. Consequently, the fresh hepatocytes from the partial liver and its cryopreserved hepatocytes expressed their intrinsic hepatic functions well and showed equal hepatotoxicity gene expression trend regardless to cryopreservation. Therefore, liver resection surgery-originated partial liver can be used as a useful source of human hepatocytes for various pharmacological and hepatotoxicity test.

• Molecular & Cellular Toxicology
• /
• 제5권1호
• /
• pp.32-43
• /
• 2009

Acetaminophen (APAP) overdose is known to cause severe hepatotoxicity mainly through the depletion of glutathione. In this study, we compared the cytotoxic effects of APAP on both a normal murine hepatic cell line, BNL CL.2, and its SV40-transformed cell line, BNL SV A.8. Gene expression profiles for APAP-treated cells were also obtained using microarray and analyzed to identify differences in genes or profiles that may explain the differences of susceptibility to APAP in these cell lines. These two cell lines exhibited different susceptibilities to APAP (0-$5,000{\mu}M$); BNL SV A.8 cells were more susceptible to APAP treatment compared to BNL CL.2 cells. A dose of $625{\mu}M$ APAP, which produced significant differences in cytotoxicity in these cell lines, was tested. Microarray analysis was performed to identify significant differentially expressed genes (DEGs) irrespective of APAP treatment. Genes up-regulated in BNL SV A.8 cells were associated with immune response, defense response, and apoptosis, while down-regulated genes were associated with catalytic activity, cell adhesion and the cytochrome P450 family. Consistent with the cytotoxicity data, no significant DEGs were found in BNL CL.2 cells after treatment with $625{\mu}M$ APAP, while cell cycle arrest and apoptosis-related genes were up-regulated in BNL SV A.8 cells. Based on the significant fold-changes in their expression, a genes were selected and their expressions were confirmed by quantitative real-time RT-PCR; there was a high correlation between them. These results suggest that gene expression profiles may provide a useful method for evaluating drug sensitivity of cell lines and eliciting the underlying molecular mechanism. We further compared the genes identified from our current in vitro studies to the genes previously identified in our lab as regulated by APAP in both C57BL/6 and ICR mice in vivo. We found that a few genes are regulated in a similar pattern both in vivo and in vitro. These genes might be useful to develop as in vitro biomarkers for predicting in vivo hepatotoxicity. Based on our results, we suggest that gene expression profiles may provide useful information for elucidating the underlying molecular mechanisms of drug susceptibility and for evaluating drug sensitivity in vitro for extrapolation to in vivo.

• 약학회지
• /
• 제40권6호
• /
• pp.727-733
• /
• 1996

2-(Allylthio)pyrazine is effective in selectively suppressing constitutive and inducible expression of cytochrome P450 2E1. The effect of 2-(allylthio)pyrazine against potentiat ed chemical injury was studied in rats. Vitamin-A pretreatment of rats substantially increased carbon tetrachloride hepatotoxicity, as supported by an ~4-fold increase in serum alanine aminotransferase (ALT) activity. Concomitant pretreatment of rats with 2-(allylthio)pyrazine at the daily dose of 200mg/kg resulted in a 76% decrease in vitamin-A-potentiated hepatotoxicity, which supported the possibility that 2-(allylthio)pyrazine protects the liver against chemical-induced hepatic injury by the mechanism associated with Kupffer cell inactivation. Pyridine pretreatment caused substantial enhancement in carbon tetrachloride hepatotoxicity. 2-(Allylthio)pyrazine treatment of rats reduced the pyridine-potentiated toxicity in a dose-dependent manner. Animals treated with both pyridine and 2-(allylthio)pyrazine prior to intoxicating dose of CCl$_4$ resulted in 85% and 47% decreases in pyridine-increased triglycerides and cholesterol levels in the liver. The protective effect of 2-(allylthio)pyrazine on the DNA strand breakage induced by benzenetriol was assessed by measuring the conversion of supercoiled ${\Phi}x$-174 DNA to the open relaxed form. 2-(Allylthio)pyrazine blocked the benzenetriol-induced conversion of supercoiled DNA to open circular form in a dose-dependent manner. The presence of 2-(allylthio)pyrazine at the doses from I to 10mM in the incubation mixture containing 5 ${\mu}$M benzenetriol completely protected benzenetriol-induced DNA strand breakage with the EC50 for the 2-(allylthio)pyrazine blocking being noted as ~220 ${\mu}$M, whereas allyl disulfide exerted protecting effect at relatively high concentrations (i.e. ~850 ${\mu}$M), suggesting that 2-(allylthio)pyrazine effectively scavenges the reactive oxygen species. These results provide evidence that 2-(allylthio)pyrazine blocks vitamin A- or pyridine-potentiated CCl$_4$ hepatotoxicity and that the agent is active in protecting DNA by scavenging the reactive oxygen species.