• Korean Journal of Clinical Pharmacy
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• v.33 no.4
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• pp.242-253
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• 2023

Background: Arrhythmia due to QT prolongation is one of the most serious adverse events with drug interactions in the elderly. This study aimed to examine the incidence of arrhythmia in Korean elderly patients who administered both cytochrome P450 3A4 (CYP3A4) substrates and inhibitors. Methods: Patients using CYP3A4 substrate and inhibitor were selected from the 2017 elderly patient dataset (the Korean Health Insurance Review and Assessment Service - Aged Population Sample). Selection criteria were patients with a medication possession ratio over 80%, medication duration of at least 7 days, and a follow-up period of 3 months or more. The patient's basic information is age, gender, health insurance type, and comorbidities. The top 50 drug pairs and comorbidity with high-incidence arrhythmia were presented. Results: In patients with drug combinations for over 7 days, there were 981 incidences of arrhythmia, and 351 incidences in those with combinations for over 30 days. The comorbidities of congestive heart failure and myocardial infarction had a significant association with incidence of arrhythmia. Among patients with 7 days or longer, the drug pairs [substrates-inhibitors] with significant adjusted odds ratio (aOR) were [propranolol-cimetidine] (aOR, 2.25; 95% confidence interval [CI], 1.66-3.04). Among patients with 30 days or longer, the drug pairs with significant aOR were [tramadol-amiodarone] (aOR, 2.87; 95% CI, 1.97-4.19). Conclusions: In elderly patients, the incidence of arrhythmia was high with drug interactions of CYP3A4 substrates and inhibitors. The comorbidity of congestive heart failure was the risk factor.

• Journal of Ginseng Research
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• v.43 no.1
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• pp.10-19
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• 2019

Background: Frequent overdose of paracetamol (APAP) has become the major cause of acute liver injury. The present study was designed to evaluate the potential protective effects of ginsenoside Rk1 on APAP-induced hepatotoxicity and investigate the underlying mechanisms for the first time. Methods: Mice were treated with Rk1 (10 mg/kg or 20 mg/kg) by oral gavage once per d for 7 d. On the 7th d, allmice treated with 250mg/kg APAP exhibited severeliverinjury after 24 h, and hepatotoxicitywas assessed. Results: Our results showed that pretreatment with Rk1 significantly decreased the levels of serum alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor, and interleukin-$1{\beta}$ compared with the APAP group. Meanwhile, hepatic antioxidants, including superoxide dismutase and glutathione, were elevated compared with the APAP group. In contrast, a significant decrease in levels of the lipid peroxidation product malondialdehyde was observed in the ginsenoside Rk1-treated group compared with the APAP group. These effects were associated with a significant increase of cytochrome P450 E1 and 4-hydroxynonenal levels in liver tissues. Moreover, ginsenoside Rk1 supplementation suppressed activation of apoptotic pathways by increasing Bcl-2 and decreasing Bax protein expression levels, which was shown using western blotting analysis. Histopathological observation also revealed that ginsenoside Rk1 pretreatment significantly reversed APAP-induced necrosis and inflammatory infiltration in liver tissues. Biological indicators of nitrative stress, such as 3-nitrotyrosine, were also inhibited after pretreatment with Rk1 compared with the APAP group. Conclusion: The results clearly suggest that the underlying molecular mechanisms in the hepatoprotection of ginsenoside Rk1 in APAP-induced hepatotoxicity may be due to its antioxidation, antiapoptosis, anti-inflammation, and antinitrative effects.

• Journal of Microbiology and Biotechnology
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• v.33 no.4
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• pp.463-470
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• 2023

This study confirmed the change in functional composition and alcohol-induced acute liver injury in Aloe arborescens after fermentation. An acute liver injury was induced by administration of ethanol (3 g/kg/day) to C57BL/6J mice for 5 days. A fermented A. arborescens Miller leaf (FAAL) extract was orally administered 30 minutes before ethanol treatment. After fermentation, the emodin content was approximately 13 times higher than that of the raw material. FAAL extract significantly attenuated ethanol-induced aspartate aminotransferase, alanine aminotransferase, and triglyceride increases in serum and liver tissue. Histological analysis revealed that FAAL extract inhibits inflammatory cell infiltration and fat accumulation in liver tissues. The cytochrome P450 2E1, superoxide dismutase, and glutathione (GSH), which involved in alcohol-induced oxidative stress, were effectively regulated by FAAL extract in serum and liver tissues, except for GSH. FAAL also maintained the antioxidant defense system by upregulating heme oxygenase 1 and nuclear factor erythroid 2-related factor 2 protein expression. In addition, FAAL extract inhibited the decrease in alcohol dehydrogenase and aldehyde dehydrogenase activity, which promoted alcohol metabolism and prevented the activation of inflammatory response. Our results suggest that FAAL could be used as a potential therapeutic agent for ethanol-induced acute liver injury.

• Journal of Microbiology and Biotechnology
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• v.20 no.11
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• pp.1563-1570
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• 2010

To construct a highly sensitive detection system for endocrine disruptors (EDs), we have compared the activity of promoters with the n-alkane-inducible cytochrome P450 gene (ALK1), isocitrate lyase gene (ICL1), ribosomal protein S7 gene (RPS7), and the translation elongation factor-1${\alpha}$ gene (TEF1) for the heterologous gene in Yarrowia lipolytica. The promoters were introduced into the upstream of the lacZ or hERa reporter genes, respectively, and the activity was evaluated by ${\beta}$-galactosidase assay for lacZ and Western blot analysis for hER${\alpha}$. The expression analysis revealed that the ALK1 and ICL1 promoters were induced by n-decane and by EtOH, respectively. The constitutive promoter of RPS7 and TEF1 showed mostly a high level of expression in the presence of glucose and glycerol, respectively. In particular, the TEF1 promoter showed the highest ${\beta}$-galactosidase activity and a significant signal by Western blotting with the anti-estrogen receptor, compared with the other promoters. Moreover, the detection system was constructed with promoters linked to the upstream of the expression vector for the hER${\alpha}$ gene transformed into the Y. lipolytica with a chromosome-integrated lacZ reporter gene under the control of estrogen response elements (EREs). It was indicated that a combination of pTEF1p-hER${\alpha}$ and CXAU1-2XERE was the most effective system for the $E_2$-dependent induction of the ${\beta}$-galactosidase activity. This system showed the highest ${\beta}$-galactosidase activity at $10^{-6}\;M\;E_2$, and the activity could be detected at even the concentration of $10^{-10}\;M\;E_2$. As a result, we have constructed a strongly sensitive detection system with Y. lipolitica to evaluate recognized/suspected ED chemicals, such as natural/synthetic hormones, pesticides, and commercial chemicals. The results demonstrate the utility, sensitivity, and reproducibility of the system for identifying and characterizing environmental estrogens.

• Archives of Pharmacal Research
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• v.21 no.2
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• pp.120-127
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• 1998

Peroxisome proliferators induce hepatic peroxisome proliferation and hepatic tumors in rodents. These chemicals increase the expression of the peroxisomal $\beta$-oxidation pathway and the cytochrome P-450 4A family, which metabolizes lipids, including eicosanoids. Peroxisome proliferators transiently induce increased cell proliferation in vivo. However, peroxisome proliferators are weakly mitogenic and are not co-mitogenic with epidermal growth factor (EGF) in cultured hepatocytes. Earlier study found that the peroxisome proliferator ciprofibrate is cornitogenic with eicosanoids. In order to study possible mechanisms of the comitogenicity of peroxisome proliferator ciprofibrate and eicosanoids' we hypothesized that the co-mitogenicity may result from synergistic or additive increases of second messengers in mitogenic signal pathways. We therefore examined the effect of the peroxisome proliferator ciprofibrate, prostaglandin $F_2_{\alpha}$($PGF_2{\alpha}$) and the combination of ciprofibrate and $PGF_2{\alpha}$ with or without growth factors on the protein kinase C (PKC) activity, and inositol-1, 4, 5-triphosphate ($IP_{3-}$) and intracellular calcium ($[Ca^{2+}]_i$) concentrations in cultured rat hepatocytes. The combination of ciprofibrate and $PGF_2{\alpha}$ significantly increased particulate PKC activity. The combination of ciprofibrate and $PGF_2{\alpha}$ also significantly increased EGF, transforming growth factor-$\alpha$ ($TGF_2{\alpha}$) and hepatic growth factor (HGF)-induced particulate PKC activity. The combination of ciprofibrate and $PGF_2_\alpha$greatly increased $[Ca^{2+}]_i$. However, the increases of PKC activity and $[Ca^{2+}]_i$ by ciprofibrate and $PGF_2{\alpha}$ alone were much smaller. Neither ciprofibrate or $PGF_2{\alpha}$ alone nor the combination of ciprofibrate and $PGF_2{\alpha}$ significantly increased the formation of $IP_3$. The combination of ciprofibrate and $PGF_2{\alpha}$, however, blocked the inhibitory effect of $TGF-{\beta}$ on particulate PKC activity and formation of $IP_3$ induced by EGF. These results show that co-mitogenicity of the peroxisome proliferator ciprofibrate and eicosanoids may result from the increase in particulate PKC activity and intracellular calcium concentration but not from the formation of $IP_3$.

• Natural Product Sciences
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• v.27 no.3
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• pp.201-207
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• 2021

We have previously reported that Acer tegmentosum extract, which is traditionally used in Korea to reduce alcohol-related liver injury, suppresses liver inflammation caused by excessive alcohol consumption and might improve metabolism. The active ingredient, 6-O-galloylsalidroside (GAL), was isolated from A. tegmentosum, and we hypothesized that GAL could provide desirable pharmacological benefits by ameliorating physiological conditions caused by alcohol abuse. Therefore, this study focused on whether GAL could ameliorate alcoholic fat accumulation and repair liver injury in mice. During chronic alcohol consumption plus binge feeding in mice, GAL was administered orally once per day for 11 days. Intrahepatic lipid accumulation was measured in vivo using a noninvasive method, ¹H magnetic resonance imaging, and confirmed by staining with hematoxylin and eosin and Oil Red O. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured using a Konelab system, and the triglyceride content was measured in liver homogenates using an enzymatic peroxide assay. The results suggested that GAL alleviated alcohol-induced steatosis,e as indicated by decreased hepatic and serum triglyceride levels in ethanol-fed mice. GAL treatment also correlated with a decrease in the Cd36 mRNA expression, thus potentially inhibiting the development of alcoholic steatosis via the hepatic de novo lipogenesis pathway. Furthermore, treatment with GAL inhibited the expression of cytochrome P450 2E1 and attenuated hepatocellular damage, as reflected by a reduction in ALT and AST levels. These findings suggest that GAL extracted from A. tegmentosum has the potential to serve as a bioactive agent for the treatment of alcoholic fatty liver and liver damage.

• Environmental Analysis Health and Toxicology
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• v.21 no.3 s.54
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• pp.291-299
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• 2006

The experiments investigated whether early exposure to testosterone propionate (TP) during prepuberty alters testis development in Sprague-Dawley male rats. We performed Hershberger assay using the stimulated weanling male rats by OECD protocols, cDNA microarray, and Western blot. TP was subcutaneously injected to uncastrated Sprague-Dawley male rat of 22 days old for 10 consecutive days at doses of 0.4, 0.8, 1.0, 1.2, 1.6 mg/kg per day. At necropsy, the following tissues were removed and weighed: combined testes, epididymides (Epi), Cowper's glands (COW), levator am, and bulbocavernosus muscles (LABC), seminal vesicles, together with coagulating gland (SV) and ventral prostate (VP). We found that TP increased the weights of Epi, VP, SV, COW, and LABC, while testis was decreased in a dose-dependent manner. In cDNA microarray analysis of testis, there were significant reductions in the expression of cytochrome P450 11A (CYP11A), the rate-limiting enzyme of steroidogenesis. Taken together these results, TP exposure before puberty in male rats may produce the delay in testis development by inhibiting the CYP11A gene expression.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.194-199
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• 2002

Many oxidative metabolites of tetrahydrocannabinols (THCs), active components of marijuana, were pharmacologically active, and 11-hydroxy-THCs, 11-oxo-${\Delta}^8$-THC, 7-oxo-${\Delta}^8$-THC, 8$\beta$, 9$\beta$-epoxyhexahydrocannabinol (EHHC), 9$\alpha$, l0$\alpha$-EHHC and 3'-hydroxy-${\Delta}^9$-THC were more active than THC in pharmacological effects such as catalepsy, hypothermia and barbiturate synergism in mice. Cannabidiol (CBD), another major component, was biotransfomred to two novel metabolites, 6-hydroxymethyl-${\Delta}^9$-THC and 3-pentyl-6, 7, 7a, 8, 9, lla-hexahydro-I, 7-dihydroxy-7, 1O-dimethyldibenzo[b, d]oxepin (PHDO) through 8R, 9-epoxy-CBD and 85, 9-epoxy-CBD, respectively. Both metabolites exhibited some pharmacological effects comparable to d9 - THe. Cannabinol (CBN), the other major component, was mainly metabolized to ll-hydroxy-CBN by hepatic microsomes of animals including humans. The pharmacological effects of the metabolite were higher than those of CBN demonstrating that II-hydroxylation of CBN is metabolic activation pathway of the cannabinoid as is the case in THCs. Tolerance and reciprocal cross-tolerance developed to pharmacological effects d8 - THC and ll-hydroxy-d8-THC , and the magnitude of tolerance development produced by the metabolite was significantly higher than that by d8-THC. The results indicate that ll-hydroxy-d8-THC has an important role not only in the pharmacological effects but also its tolerance development of d8 - THe. THCs and their metabolites competed to the specific binding of CP-55, 940, an agonist of cannabinoid receptor, to synaptic membrane from bovine cerebral cortex. The Ki value of THCs and their metabolites were closely paralleled to their pharmacological effects in mice. A novel cytochrome P450 (cyp2c29) was purified and identified as a major enzyme responsible for the metabolic activation of d8-THC at the II-position in the mouse liver. cDNA of CYP2C29 was cloned from a mouse cDNA library and its sequence was determined. The oxidation mechanism of THC by cyp2c29 was proposed.

• Environmental Analysis Health and Toxicology
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• v.6 no.3_4
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• pp.105-121
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• 1991

The object of this study is to investigate the toxicity of fenvalerate [(RS)-$\alpha$-cyano-3 -phonoxybenzyl-(RS)-2-(4-ch1orophenyl)-3-methylbutyrate] and the effect of carbaryl on the toxicity of fenvalerate. Rats were treated with fenvalerate (50 mg/kg, 100 mg/kg), carbaryl (50 mg/kg, 100 mg/kg) or mixtures of the two compounds (fenvalerate+carbaryl: 50 mg/kg+50 mg/kg, 50 mg/kg+100 mg/kg) by oral administration for 1~3 weeks. Control groups were treated with corn oil. The experimental results were summarized as follows. 1. LD$_{50}$ values of fenvalerate and carbaryl in male rats were 385 mg/kg and 625 mg/kg respectively. When 50 mg/kg and 100 mg/kg of carbaryl were administratrd, LD$_{50}$values of fenvalerate were 265 mg/kg and 225 mg/kg respectively. 2. Biochemical parameters such as ALT, LDH and glucose in serum were much more increased in the groups treated with mixture than the groups treated with either one of fenvalerate or carbaryl. 3. The groups treated with carbaryl and mixture for 3 weeks, the contents of cytochrome P-450 in the liver were significantly increased. In renal microsomal fractions, however, no significant changes of drug metabolizing enzyme activities were observed. 4. The activities of aniline hydroxylase in hepatic microsomal fractions were increased in the groups treated with fenvalerate and mixture and activity was much more increased in the groups treated with mixture. 5. The activities of ATPase in the groups treated with fenvalerate were decreased than that of groups treated with mixture. TBA values and the activity of glucose-6 -phosphatase in the liver were not significantly changed. 6. In mixture treated groups, the activities of cholinesterase in serum and in the liver were more decreased than those of carbaryl treated groups. The activities of carboxylesterase in serum in the liver were slightly increased in mixture treated groups, but in fenvalerate treated groups, the activities of carboxylesterase were much more increased than those of control groups. 7. As a result of this study, when carbaryl was as the synergist of fenvalerate, carbaryl inhibited the activities of esterases, so the toxicity of fenvalerate was increased.sed.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.2
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• pp.781-784
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• 2016

The Plurinational State of Bolivia (Bolivia) has a high incidence rate of gallbladder cancer (GBC). However, the genetic and environmental risk factors for GBC development are not well understood. We aimed to assess whether or not cytochrome P450 (CYP1A1), glutathione S-transferase mu 1 (GSTM1), theta 1 (GSTT1) and tumor suppressor protein p53 (TP53) genetic polymorphisms modulate GBC susceptibility in Bolivians. This case-control study covered 32 patients with GBC and 86 healthy subjects. GBC was diagnosed on the basis of histological analysis of tissues at the Instituto de Gastroenterologia Boliviano-Japones (IGBJ); the healthy subjects were members of the staff at the IGBJ. Distributions of the CYP1A1 rs1048943 and TP53 rs1042522 polymorphisms were assayed using PCR-restriction fragment length polymorphism assay. GSTM1 and GSTT1 deletion polymorphisms were detected by a multiplex PCR assay. The frequency of the GSTM1 null genotype was significantly higher in GBC patients than in the healthy subjects (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.03-5.37; age-adjusted OR, 3.53; 95% CI, 1.29-9.66; age- and sex-adjusted OR, 3.40; 95% CI, 1.24-9.34). No significant differences were observed in the frequencies of CYP1A1, GSTT1, or TP53 polymorphisms between the two groups. The GSTM1 null genotype was associated with increased GBC risk in Bolivians. Additional studies with larger control and case populations are warranted to confirm the association between the GSTM1 deletion polymorphism and GBC risk suggested in the present study.