• 대한약리학회지
• /
• 제21권1호
• /
• pp.1-11
• /
• 1985

이물질(xenobiotics) 대사에 관여하는 간장 microsome과 cytosol 효소 활성에 indole, indole-3-carbinol 및 benzofuran이 미치는 영향을 검색하기위하여 마우스에 이들 약물을 각각 5 mmole/kg씩 10일간 투여하여 다음 몇 가지의 성적을 얻었다. Benzofuran은 microsome 효소인 aniline hydroxylase, 7-ethoxycoumarin O-deethylase, p-nitrophenol UDPGA-transferase, epoxide hydrolase와 cytosol 효소인 glutathione S-tranferase, NADH : quinone reductase, UDP-glucose dehydrogenase의 활성도를 증가시켰다. 그러나 benzofuran과는 구조적으로 furan ring내의 N원소가 O원소로 치환되었을 뿐 주된 구조가 유사한 indole과 indole-3-carbinol 투여로는 UDPGA-transferase와 NADH: quinone reductase의 활성도 증가를 볼 수 없었으며, 특히 indole은 NADPH : cytochrome C reductase만을 증가시킨데 비하여 구조상 indole에 carbinol (methanol)기가 붙은 indole-3-carbinol은 수종의 mixed function oxidase와 아울러 특히 epoxide hydrolase의 활성도 역시 증가시켰다. 이러한 결과는 benzofuran과 indole-3-carbinol에 의한 epoxide hydrolase 활성도 증가의 기전의 일부를 설명할 수 있을 것으로 생각된다.

• Archives of Pharmacal Research
• /
• 제23권6호
• /
• pp.620-625
• /
• 2000

The mechanisms of liver injury from cold storage and reperfusion are not completely under-stood. The aim of the present study was to investigate whether the inactivation of Kupffer cells (KCs) by gadolinium chloride ($GdCl_3$) modulates ischemia-reperfusion injury in the rat liver. Hepatic function was assessed using an isolated perfused rat liver model. In livers subjected to cold storage at $4^{\circ}C$ in University of Wisconsin solution for 24 hrs and to 20 min rewarm-ing ischemia, oxygen uptake was markedly decreased, Kupffer cell phagocytosis was stimulated, releases of purine nucleoside phosphorylase and lactate dehydrogenase were increased as compared with control livers. Pretreatment of rats with $GdCl_3$) , a selective KC toxicant, suppressed kupffer cell activity, and reduced the grade of hepatic injury induced by ischemia-reperfusion. While the initial mixed function oxidation of 7-ethoxycoumarin was not different from that found in the control livers, the subsequent conjugation of its meta-bolite to sulfate and glucuronide esters was suppressed by ischemia-reperfusion, CdCl$_3$restored sulfation and glucuronidation capacities to the level of the control liver. Our findings suggest that Kupffer cells could play an important role in cold/warm ischemia-reperfusion hepatic injury.

• Journal of Microbiology and Biotechnology
• /
• 제16권2호
• /
• pp.295-298
• /
• 2006

Actinomycetes are ubiquitous Gram-positive soil bacteria and a group of the most important industrial microorganisms for the biosynthesis of many valuable secondary metabolites as well as the source of various bioconversion enzymes. Cytochrome P450 hydroxylase (CYP), a hemebinding protein, is known to be involved in the modification of various natural compounds, including polyketides, fatty acids, steroids, and some aromatic compounds. Previously, six different novel CYP genes were isolated from a rare actinomycetes called Sebekia benihana, and they were completely sequenced, revealing significant amino acid similarities to previously known CYP genes involved in Streptomyces secondary metabolism. In the present study, these six CYP genes were functionally expressed in Streptomyces lividans, using an $ermE^{*}$ promoter-containing Streptomyces expression vector. Among six CYP genes, two S. benihana CYP genes (CYP503 and CYP504) showed strong hydroxylation activities toward 7-ethoxycoumarin. Furthermore, the recombinant S. lividans containing both the S. benihana CYP506-ferredoxin genes as well as the S. coelicolor feredoxin reductase gene also demonstrated cyclosporin A hydroxylation activity, suggesting potential application of actinomycetes CYPs for the biocatalysts of natural product bioconversion.

• Journal of Nutrition and Health
• /
• 제38권9호
• /
• pp.689-697
• /
• 2005

This study was conducted to fine out the preventive effects of chitosan and chitosan oligomer on the disorders of hepatic functions and lipid metabolism induced by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) using adult male rats (SD) for four weeks. Rats were fed chitosan ($4\%$) or chitosan oligomer ($4\%$) diets respectively before 3weeks of TCDD treatment (50 ug/kg BW) by intraperitoneal injection and then continually supplied these diets for one week until being sacrificed. The elevation of serum total and LDL cholesterol levels induced by TCDD treatment was significantly reduced in the rats fed chitosan diets. The increment of liver triglyceride levels caused by TCDD treatment was tended to suppress in all rats fed chitosan and chitosan oligomer diets. Fecal total lipid and cholesterol excretion were high levels in the rats fed chitosan diets. The hepatic cytosolic catalase activities significantly decreased by TCDD treatment appeared recovering trend by chitosan diets. In hepatic microsomal cytochrome p-450, NADPH cytochrome p-450 reductase, ethoxycoumarin-o-deethylase (ECOD) and benzphetamin N-demethylase (BPND) chitosan than chitosan oligomer diets apparently decreased the increasing levels by TCDD treatment. In histochemical observation the fat droplets and apoptosis of hepatocytes by TCDD treatment were markedly alleviated by chitosan and chitosan oligomer diets. These results indicate that chitosan, more than chitosan oligomer can exert preventive effects on some disorders of hepatic functions and lipids accumulation by TCDD.

• 한국응용약물학회:학술대회논문집
• /
• 한국응용약물학회 1993년도 제2회 신약개발 연구발표회 초록집
• /
• pp.97-97
• /
• 1993

본 연구과제에서는 적출판류간실험법 (isolated perfused liver technique)을 약물의 간독성 유발 및 보간작용에 관한 실험법으로 개발하고자 butylated hydroxyanisole (BHA) 을 이용하여 보간실험을 하였다. BHA를 식이투여한 흰쥐로부터 적출한 간에 간독성 모델물질로 2,6-dichlorophenolindophenol (DCPIP) 을 관류시켜 관류액내의 DCPIP의 유리형, 환원형, glucuronide, sulfate 포합체의 대사체를 측정하여 DCPIP 외 대사양상을 관찰하였으며, 동시에 간세포 손상으로 관류액내로 유출된 lactate dehydrogenase (LDH)의 활성도를 측정하여 DCPIP예 의할 간세포독성 유발정도를 간접적으로 측정하여 대조군과 비교하였다. 그리고 BHA에 의한 보간작용이 약물대사효소의 변와에 기인한 것인가를 관찰하기 위하여 모델약물로 7-ethoxycoumarin (EC) 이나 EC의 phase I 대사산물인 7-hydroxycoumarin (HC) 을 관류시켜 관류액내의 HC의 유리체, glucuronide 포합체, sulfate 포합체로의 대사량을 측정하여 약물대사시 약물의 활성화에 관계하는 phase I mixed function oxidase (MFO) 효소와 약물의 해독화에 관계하는 phase II 포합효소 (UDP-glucuronyltranesferase(UDPGT)와 sulfotransferase (ST))의 활성도 변화를 측정하여 대조군과 비교하였다. 간독성 모델물질인 DCPIP를 적출한 흰쥐의 간에 관규시켰을때 BHA 전처리군이 LDH가 유출되기 시작하는 시간이 대조군에 비하여 유의적으로 늦었으며, LCH가 유출량도 유의적으로 감소되어 DCPIP에 의한 간독성 유발능력이 BHA에 의하여 감소됨을 관찰하였다. 아울러 DCPIP의 대사체중 환원체와 glucuronide 포합체의 생성량이 증가되어 BHA에 의하여 quinone reductase와 UDPGT 활성도가 증가되었음을 알 수 있었다. 그리고 BHA 전처리에 의하여 MFO효소계와 ST의 활성도에는 변화가 없었으나 UDOGT 의 활성도는 약 2.2배 증가되었다. 이상의 결과로 BHA에 의한 보간작용은 간독성 물질을 활성화시키는 phase I MFO 효소의 활성도에는 변화없이 해독작용에 관여하는 phase II효소들의 활성도 증가에 기인된 것을 알 수 있었다. 그리고 이러한 결과는 적출한 관류간실험법은 여러 약물의 보간효과를 관찰하는 실험법으로 적합할 것으로 사료되었다.

• 한국연초학회지
• /
• 제20권1호
• /
• pp.99-107
• /
• 1998

Numerous studies have demonstrated a negative association between cigarette smoking and Parkinson's disease. The present study was undertaken to investigate whether chronic exposure of mice to cigarette smoke a(footed the metabolism of 1-methyl-1113,6-tetrahydro-pyridine (MPTP) by cytochrome P4SO (P-450) or flavin-containing monooxygenase (FMO) in the hepatic microsomes of C57BL6/J mice. Adult male C57BL6/J mice were exposed to mainstream smoke generated from 15 cigarettes for 10 min a day and 5 day per week for 6 weeks. MPTP (10 mg/kg body weight) was administered to mice by subcutaneous injection for 6 consecutive days. Microsolnal P-450 content was increased by MPTP, smoke exposure, or both, but NADPH cytochrome P-450 reductase activity was rather decreased by the same treatments. The activities of benzo(a)pyrene hydroxylase, 7-ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase were significantly increased by the exposure of cigarette smoke, but were not or little affected by MPTP treatment. Benzphetamine N-demethylase activity was not affected either by MPTP treatment or by cigarette smoke exposure, but it was significantly increased by the combined MPTP treatment with cigarette smoke exposure, showing their synergic effect for the induction of the enzyme activity. Interestingly, in vitro studies of hepatic FMO and P-450 system both O-oxygenation and N-demethylation of MPTP were increased in the smoke-exposed or in the MPTP-treated mice. These results suggest that the enhancement in the N-demethylation as well as O-deethylation of P-450 system and in the N-oxygenation of FMO activity by cigarette smoke exposure in mouse liver may contribute to attenuating the neurotoxic effects of MPTP on the nigrostriatal dopaminergic neurons.