• The Korean Journal of Physiology and Pharmacology
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• v.4 no.6
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• pp.471-477
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• 2000

In the rabbit renal artery, acetylcholine $(ACh,\;1\;nM{\sim}10\;{\mu}M)$ induced endothelium-dependent relaxation of arterial rings precontracted with norepinephrine $(NE,\;1\;{\mu}M)$ in a dose-dependent manner. $N^G-nitro- L-arginine$ (L-NAME, 0.1 mM), an inhibitor of NO synthase, or ODQ $(1\;{\mu}M),$ a soluble guanylate cyclase inhibitor, partially inhibited the ACh-induced endothelium-dependent relaxation. The ACh-induced relaxation was abolished in the presence of 25 mM KCl and L-NAME. The cytochrome P450 inhibitors, 7- ethoxyresorufin $(7-ER,\;10\;{\mu}M),$ miconazole $(10\;{\mu}M),$ or 17-octadecynoic acid $(17-ODYA,\;10\;{\mu}M),$ failed to inhibit the ACh-induced relaxation in the presence of L-NAME. 11,12-epoxyeicosatrienoic acid $(11,12-EET,\;10\;{\mu}M)$ had no relaxant effect. The ACh-induced relaxation observed in the presence of L-NAME was significantly reduced by a combination of iberiotoxin $(0.3\;{\mu}M)$ and apamin $(1\;{\mu}M),$ and almost completely blocked by 4-aminopyridine (5 mM). The ACh-induced relaxation was antagonized by $P_{2Y}$ receptor antagonist, cibacron blue $(10\;and\;100\;{\mu}M),$ in a dose-dependent manner. Furthermore, 2-methylthio-ATP (2MeSATP), a potent $P_{2Y}$ agonist, induced the endothelium-dependent relaxation, and this relaxation was markedly reduced by either the combination of iberiotoxin and apamin or by cibacron blue. In conclusion, in renal arteries isolated from rabbit, ACh produced non-NO relaxation that is mediated by an EDHF. The results also suggest that ACh may activate the release of ATP from endothelial cells, which in turn activates $P_{2Y}$ receptor on the endothelial cells. Activation of endothelial $P_{2Y}$ receptors induces a release of EDHF resulting in a vasorelaxation via a mechanism that involves activation of both the voltage-gated $K^+$ channels and the $Ca^{2+}-activated\;K^+\;channels$. The results further suggest that EDHF does not appear to be a cytochrome P450 metabolite.

• The Korean Journal of Physiology and Pharmacology
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• v.3 no.1
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• pp.83-91
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• 1999

Angiotensin II (ANG II) has a biphasic effect on $Na^+$ transport in proximal tubule: low doses of ANG II increase the $Na^+$ transport, whereas high doses of ANG II inhibit it. However, the mechanisms of high dose ANG II-induced inhibition on $Na^+$ uptake are poorly understood. Thus the aim of the present study was to investigate signal transduction pathways involved in the ANG II-induced inhibition of $Na^+$ uptake in the primary cultured rabbit renal proximal tubule cells (PTCs) in hormonally defined serum-free medium. ANG II $(10^{-9}\;M)-induced$ inhibition of $Na^+$ uptake was blocked by losartan $(10^{-8}\;M,\;AT_1\;antagonist),$ but not by PD123319 $(10^{-8}\;M,\;AT_2\;antagonist)$ (P<0.05). ANG II-induced inhibition of $Na^+$ uptake was also completely abolished by neomycin $(10^{-4}\;M,$ PLC inhibitor), W-7 $(10^{-4}\;M,$ calmodulin antagonist), and $AACOCF_3\;(10^{-6}\;M,\;PLA_2\;inhibitor)$ (P<0.05). ANG II significantly increased $[^3H]arachidonic$ acid (AA) release compared to control. The ANG II-induced $[^3H]AA$ release was blocked by losartan, $AACOCF_3,$ neomycin, and W-7, but not by PD123319. ANG II-induced $[^3H]AA$ release in the presence of extracellular $Ca^{2+}$ was greater than in $Ca^{2+}-free$ medium, and it was partially blocked by TMB-8 $(10^{-4}\;M,$ intracelluar $Ca^{2+}$ mobilization blocker). However, in the absence of extracellular $Ca^{2+},$ it was completely blocked by TMB-8. In addition, econazole $(10^{-6}\;M,$ cytochrome P-450 monooxygenase inhibitor) and indomethacin $(10^{-6}\;M,$ cyclooxygenase inhibitor) blocked ANG II-induced inhibition of $Na^+$ uptake, but NGDA $(10^{-6}\;M,$ lipoxygenase inhibitor) did not affect it. In conclusion, $PLA_2-mediated$ AA release is involved in ANG II-induced inhibition of $Na^+$ uptake and is modulated by $[Ca^{2+}]_i$ in the PTCs.

• YAKHAK HOEJI
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• v.55 no.3
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• pp.251-259
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• 2011

Cigarette smoke condensate (CSC) is known to be carcinogenic compound. CSC contains many organic compounds such as polycyclic aromatic hydrocarbons (PAHs), and heterocyclic amine compounds (HCAs). Reactive oxygen species (ROS) are also generated and induce oxidative DNA damage during the metabolism of CSC. The rat microsome mediated and DNA repair enzyme treated comet assays together with conventional comet assay were performed to evaluate the mechanisms of CSC genotoxicity. The organic extract of CSC induced oxidative and microsome mediated DNA damage. Vitamin C as a model antioxidant reduced DNA damage in endonuclease III treated comet assay. One of flavonoid, galangin as a CYP1A1 inhibitor, reduced DNA damage in the presence of S-9 mixture. The ethanol extracts of the mixed vegetables (BV) or the mixed fruits (BF) showed potent inhibitory effects against CSC induced DNA damage with oxidative DNA lesions and in the prescence of S-9 mixture. These results indicate that BV and BF could prevent CSC-induced cellular DNA damage by inhibiting oxidative stress and suppressing cytochrome P450 in mammalian cells.

• Korean Journal of Environmental Biology
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• v.22 no.1
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• pp.177-183
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• 2004

Cytochrome P45O (CYP) contents and 7-ethoxyresorufin-O-deethylase (EROD) activity were determined in hepatic microsome of olive flounder (Paralichthys olivaceus) exposed to tributyltin chloride (TBTC), tributyltin oxide (TBTO), and triphenyltin chloride (TPTC). In addition, effects of in vivo (intraperitoneal injection of 7.5 mg $kg^{-1}$ BW) exposure of flounder to TPTC on CYP, NADPH cytochrome c reductase, NADH cytochrome b5 yeductase and EROD levels were measured. In in vitro exposure of hepatic microsome to organotins, TBTC, TBTO and TPTC reduced CYP contents and inhibited EROD activity. The TPTC was the strongest inhibitor, which is followed by TBTO and TBTC. The degree of inhibition, especially EROD acitivity, depended on the exposure duration. In addition, all the target enzymes in flounder were inhibited by TPTC with the in vivo exposure to TPTC. As EROD activity was the most sensitive to the inhibitions and demonstrated good reproducibility of the results, it could be used as a helpful tool toy monitor effects of organotin compounds on mixed funciton oxygenase system in marine fish.

• Biomolecules & Therapeutics
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• v.28 no.4
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• pp.361-369
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• 2020

Tofacitinib, a Janus kinase inhibitor, was developed for the treatment of rheumatoid arthritis. Recently, it has been associated with an increased change in arthritis development in patients with diabetes. Herein, we evaluated the pharmacokinetics of tofacitinib after intravenous (10 mg/kg) and oral (20 mg/kg) administration to rats with streptozotocin-induced diabetes mellitus and control rats. Following intravenous administration of tofacitinib to rats with streptozotocin-induced diabetes mellitus, area under the plasma concentration-time curve from time zero to infinity of tofacitinib was significantly smaller (33.6%) than that of control rats. This might be due to the faster hepatic intrinsic clearance (112%) caused by an increase in the hepatic cytochrome P450 (CYP) 3A1(23) and the faster hepatic blood flow rate in rats with streptozotocin-induced diabetes mellitus than in control rats. Following oral administration, area under the plasma concentration-time curve from time zero to infinity of tofacitinib was also significantly smaller (55.5%) in rats with streptozotocin-induced diabetes mellitus than that in control rats. This might be due to decreased absorption caused by the higher expression of P-glycoprotein and the faster intestinal metabolism caused by the higher expression of intestinal CYP3A1(23), which resulted in the decreased bioavailability of tofacitinib (33.0%) in rats with streptozotocin-induced diabetes mellitus. In summary, our findings indicate that diabetes mellitus affects the absorption and metabolism of tofacitinib, causing faster metabolism and decreased intestinal absorption in rats with streptozotocin-induced diabetes mellitus.

• The Korean Journal of Mycology
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• v.13 no.4
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• pp.203-212
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• 1985

Of 450 strains isolated from the soil microbes collected in various locations in Korea, a strain had a strong inhibitory activity against bacterial ${\alpha}-amylase$ and was named strain DMC-72 of the genus Streptomyces. The amylase inhibitory metabolite produced by this strain was purified by means of acetone precipitation, adsorption on Amberlite IRC-50 and SP-Sephadex C-25. The inhibitor was found to be a derivative of oligosaccharides by spectral and chemical data. The inhibitor was stable at the pH range of $1{\sim}13$ and at $100^{\circ}C$ for half an hour, also inhibited other amylases such as salivary ${\alpha}-amylase$, pancreatic ${\alpha}-amylase$, fungal ${\alpha}-amylase$ and glucoamylase. However, it showed no inhibitory activity against ${\alpha}-glucosidase$, ${\beta}-glucosidase$, dextranase, and ${\beta}-amylase$. The kinetic studies of the inhibitor showed that its inhibitory effects on starch hydrolysis by ${\alpha}-amylase$ were noncompetitive.

• YAKHAK HOEJI
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• v.43 no.4
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• pp.481-486
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• 1999

Excessive or long term ingestion of alcohol may cause hepatitis, cirrhosis, hepatic tumor and so on. Aldehyde and active form of free oxygen that are metabolites of alcohol in liver are the cause of liver cell damage. The main system of alcohol metabolism is composed of alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH) and cytochrome P450. In connection with in vivo alcohol metabolism, more than one hundred natural products were screened for inhibition or activation of alcohol dehydrogenase. As a results, we found significant inhibition ($IC_50$) of ADH by methanolic extracts of Puerariae Radix ($61.2{\;}\mu\textrm{g}/ml$), Glycyrrhizae Radix ($105.0{\;}\mu\textrm{g}/ml$), Cinnamomi Ramulus ($7.0{\;}\mu\textrm{g}/ml$), Rhei Rhizoma ($36.7{\;}\mu\textrm{g}/ml$), Mori Cortex Radicis ($106.2{\;}\mu\textrm{g}/ml$), Chrysanthemi Flos ($112.2{\;}\mu\textrm{g}/ml$), Erycibes Caulis ($36.7{\;}\mu\textrm{g}/ml$), and Scutellariae Radix ($122.5{\;}\mu\textrm{g}/ml$)

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.149.1-149.1
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• 2003

We have previously shown that 2,4,3',5'-tetramethoxystilbene (TMS), a synthetic trans-stilbene analogue, is one of the most potently selective inhibitor of human cytochrome P450 1B1 in vitro and in vivo. In the present studies, the apoptotic effects of TMS were investigated in HL-60 cells. The effects of TMS on the proliferation of HL-60 cells were determined with MTT assay. TMS exhibited cytotoxicity with an $IC_50$ value of 37 nM. Cotreatment with TMS and etoposide, a well-known anticancer drug significantly enhanced the cytotoxicity. (omitted)

• YAKHAK HOEJI
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• v.59 no.2
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• pp.59-65
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• 2015

KR-67500, trans-4-(2-(4-methyl-1,1-dioxido-6-(2,4,6-trichlorophenyl)-1,2,6-thiadiazinan-2-yl)acetamido)adamantane-1-carboxamide, is a novel $11{\beta}$-HSD1 inhibitor with its therapeutic effects of its anti-diabetic, anti-adipogenic and anti-osteoporotic activity. This study was performed to evaluate in vitro and in vivo pharmacokinetic properties of KR-67500 as a new drug candidate. KR-67500 was stable and highly bound to proteins in rat plasma. The microsomal stabilities of KR-67500 in human and rat liver were high. The inhibitory effect of KR-67500 for five cytochrome P450 enzymes was low. Preclinical pharmacokinetic studies have been carried out with intravenous or oral administrations of KR-67500 (10 mg/kg) to male rats and monkey. KR-67500 showed low clearance (0.68 l/h/kg) and high oral bioavailability (102%) in male rats. These results suggest that KR-67500 has good drug-like pharmacokinetic properties with a low first-pass effect and high bioavailability for an oral therapeutic agent of diabetes and osteoporosis.

• Biomolecules & Therapeutics
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• v.16 no.3
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• pp.190-196
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• 2008

Deoxypodophyllotoxin (DPT) is a medicinal herb product isolated from Anthriscus sylvestris. DPT possesses beneficial activities in regulating immediate-type allergic reaction and anti-inflammatory activity through the dual inhibition of cyclooxygenase-2 and 5-lipoxygenase. In the present study, the metabolism of DPT was further characterized in rat liver microsomes isolated from male Sprague Dawley rats. The metabolism of DPT was NADPH-dependent. In addition, when liver microsomes were incubated with SKF-525A, a well-known CYP inhibitor, in the presence of $\beta$-NADPH, the metabolism of DPT was significantly inhibited. Using enriched rat liver microsomes, the anticipated isoforms of cytochrome P450s (CYPs) in the metabolism of DPT were partially characterized. Phenobarbital-induced microsomes increased in the formation of metabolite M1. The metabolite M3 was only produced in the enriched microsomes isolated from dexamethasone-treated rats. The results indicated that the metabolism of DPT would be CYP-dependent and that CYP2B and CYP3A might be important in the metabolism of DPT in rats.