청목향 Aristolochiae radix에 있어 F344 랫드의 독성

김충용,김용범,양병철,이종화,정문구,양기화,장동덕,한상섭,강부현,Kim, Choong-Yong,Kim, Yong-Bum,Yang, Byung-Chul,Lee, Jong-Hwa,Chung, Moon-Koo,Yang, Ki-Hwa,Jang, Dong-Deuk,Han, Sang-Seop,Kang, Boo-Hyon 대한수의학회 2005 大韓獸醫學會誌 Vol.45 No.1

13-week orally repeated dose toxicity was investigated to ascertain the toxic effects of Aristolochiae radix in F344 rats at dose levels of 0, 1 (0.003 AA, aristolochic acid, mg/kg), 5 (0.014 AA mg/kg), 25 (0.068 AA mg/kg), 125 (0.34 AA mg/kg), and 500mg/kg (AA 1.36 mg/kg). No mortalities were found in any of the dose groups including vehicle control groups of both sexes during the study period. Hematologic and serum biochemical examinations revealed no changes related to the test item in any of the dose groups of both sexes. However, gross findings at necropsy implicated thickening of the stomach wall. In histopathological examinations, prominent findings related to the test item treatment were observed in the stomach and urinary bladder. There were squamous cell papilloma, squamous cell hyperplasia, ulceration and erosion observed in the non-glandular stomach. Squamouse cell hyperplasia was observed at dose levels of more than 125 mg/kg in both sexes and squamous cell papilloma was observed at dose level of 500 mg/kg in both sexes. The incidence and severity of these proliferating lesions including squamous cell hyperplasia and squamous cell papilloma increased with dose dependency. Transitional cell hyperplasia was also observed in the urinary bladder at dose levels of more than 25 mg/kg in both sexes and the incidence and severity of the lesion increased with dose dependency. In conclusion, the toxic changes related to the test item treatment were observed in the stomach and urinary bladder, and the no-observed-adverse-effect level (NOAEL) was estimated to be 5 mg/kg/day for both males and females in F344 rats.

Formaldehyde 가스 흡입에 의한 마우스의 급성독성 및 소핵 유발성에 관한 연구

김충용,김균,심점순,김용화,노정구,Kim, Choong-Yong,Kim, Kyun,Shim, Jeom-Soon,Kim, Yong-Hwa,Roh, Jung-Koo 한국독성학회 1991 Toxicological Research Vol.7 No.1

The acute and genetic effect of formaldehyde on mice through inhalation route was studied. The Riley's chamber with one stack of cage was used for the exposure and the micronucleus test was performed under unprecedently maximum exposure concentration. LC50's of formaldehyde in mice by whole body exposure for 4 hours were 105.5 ppm with 95% confidence interval of 72.6 ppm and 143.2 ppm for male, and 159.2 ppm with 95% confidence interval of 116.5 ppm and 272.7 ppm for female. Cinicial symptoms by acute exposure were salivation, lacrimation, and abnormal respiration.

게잡이 원숭이에 있어 rHuEPO의 4주간 투여 후 혈액학 및 조직병리학적 변화

김충용(Choong-Yong Kim),윤석주(Seok-Joo Yoon),김용범(Yong-Bum Kim),하창수(Chang-Su Ha),김달현(Dal-Hyun Kim),권명상(Myung-Sang Kwon),한상섭(Sang-Seop Han) 한국독성학회 2005 Toxicological Research Vol.21 No.3

We investigated effects of recombinant human erythropoietin (rHuEPO) on body weight, organ weight, hematology, serum biochemistry, and histopathology in 6 male cynomolgus monkeys (Macaca fascicularis). Six monkeys, composed of treatment and control groups, were intravenously administered 3 times per week at doses of 0 and 2730 IU/ 0.1 ㎖/㎏ with rHuEPO for 4 weeks. rHuEPO treatment did not show any change in body weights for 4 weeks and caused an increase of organ weight in spleen, salivary gland, kidney, and liver. rHuEPO treatment increased significantly mean corpuscular hemoglobin concentration, reticulocyte, and red cell distribution width from day 3 of the study and red blood cells, hemoglobin, and hematocrit levels were increased significantly from day 7 or 10 up to day 28. For an increase in red cell distribution width, it was found to a large extent on day 7, day 10, and day 14, while was found to a small extent on day 21 and day 28. It increased platelet distribution width on day 10, day 14, day 21, and day 28. Histopathological examination showed that rHuEPO treatment caused an extramedullary hemopoiesis in spleen and bone marrow hyperplasia in sternum and femur. The results indicated that rHuEPO treatment caused an increase in platelet-and RBC-related parameters, extramedullary hemopoiesis of spleen, and bone marrow hyperplasia of sternum and femur. The present study will be valuable in the proper interpretation and validation of general toxicology studies for biogeneric drugs including rHuEPO in cynomolgus monkeys.

Cynomolgus Monkey에 있어 혈액학 및 혈액생화학적 지표

김충용(Choong-Yong Kim),이현숙(Hyun-Sook Lee),한수철(Su-Cheol Han),허정두(Jeong-Doo Heo),하창수(Chang-Su Ha),권명상(Myung-Sang Kwon),정문구(Moon-Koo Chung) 한국실험동물학회 2004 Laboratory Animal Research Vol.20 No.1

To provide basic information on blood for safety assessment, physiological levels of hematology and serum chemistry were ascertained in nineteen male (average body weight, 2.86 ㎏) and sixteen female (average body weight, 2.73 ㎏) cynomolgus monkeys. Hematologic parameters included fourteen items including red blood cells (RBC) hemoglobin (Hb), hematocrit (HCT), white blood cells (WBC) and differential leukocyte counts (%WBC). Serum biochemical parameters included twenty items including alkaline phosphatase (ALP), creatinine (CREA), creatine phosphokinase (CPK), triglyceride (TG), inorganic phosphorous (IP), etc. Hematological levels showed great variation in platelet, reticulocyte and WBC, whereas showed less variation in RBC, Hb, and HCT. Serum biochemical levels showed great variation in aspartate aminotransferase (AST), alanine aminotransferase (ALT), ALP, Blood urea nitrogen (BUN), glucose (GLU), total cholesterol (TCHO), CPK, TG, total bilirubin (TBIL), phospholipid (PL) and inorganic phosphate (IP), whereas showed less variation in albumin/globulin ratio (A/G ratio), total protein (TP), albumin (ALB), sodium (Na), potassium (K), chloride (Cl). Hematological determined showed greater values of Hb, and HCT in males than in females, while serum biochemical assay showed greater values of ALP, CPK and IP in males than in females. The present study will be valuable in the proper interpretation and validation of general toxicology studies using cynomolgus monkeys.

실험동물을 이용한 GLP 독성평가

김충용(Kim Choong-Yong) 한국실험동물학회 2004 한국실험동물학회 학술발표대회 논문집 Vol.2004 No.-

Effects of glutathione (GSH) on cadmium (Cd) distribution to the kidney

김충용(Choong Yong Kim),이원창(Won Chang Lee),이상목(Sang Mok Lee),김진석(Jin Suk Kim) 한국예방수의학회 1998 예방수의학회지 Vol.22 No.3

글루타티온은 3개의 아미노산으로 구성된 물질로서 간에서 독성물질에 대한 항산화작용은 물론 해독작용에 관여하는 것으로 잘 알려져 있으나, 이는 수은과 같은 중금속을 신장으로 수송시키는 운송담체로서의 기능도 동시에 하고 있음이 보고되고 있다. 따라서, 본 연구에서는 카드뮴 투여 직후 조직내 카드뮴의 분포에 미치는 글루타티온의 영향에 대하여 조사하였다. 마우스에 카드뮴 (3mg/kg 또는 6mg/kg)과 외인성 글루타티온을 동시에 투여후 조직내 카드뮴의 농도를 측정하였다. 그 결과 간에서는 그 농도가 글루타티온의 투여와는 관계없이 카드뮴이 축적되었으나, 신장에서는 글루타티온 동시투여에 의해 4.7배 및 6배로 각기 카드뮴의 농도를 증가시키는 결과가 관찰되었다. 따라서 혈중 고농도의 글루타티온이 신장의 카드뮴 축적을 촉진시키고 있음을 알 수 있었다. 한편 간의 내인성 글루타티온이 감소된 경우, 즉 간의 글루타티온 고갈제인 DCNB를 전 투여한 상태에서 카드뮴을 투여한 결과, 간 및 신장의 카드뮴 농도는 카드뮴만 투여된 그룹과 유의성이 없음이 관찰되어 카드뮴 투여 직후 신장의 카드뮴 축적에서는 외인성 글루타티온, 즉 혈중 고농도의 글루타티온 존재시 만이 신장 카드뮴 농도의 증가를 촉진시키는 것을 알 수 있었다.

게잡이 원숭이에 있어 rHuEPO(HM10760)의 단회 투여 후 혈액학 및 혈액생화학적 변화

김충용(Choong-Yong Kim),이현숙(Hyun-Sook Lee),이필수(Pil-Soo Lee),하창수(Chang-Su Ha),권세창(Se-Chang Kwon),이관순(Gwan Sun Lee),송창우(Chang-Woo Song),한상섭(Sang-Seop Han) 한국독성학회 2006 Toxicological Research Vol.22 No.1

Changes in hematology and serum biochemistry after treatment of recombinant human erythropoietin (rHuEPO, HM10760) were screened in 4 male cynomolgus monkeys (Macaca fascicularis). Four monkeys, composed of a treatment group of HM10760 and a positive control group of Aranesp<SUP>®</SUP>, were subcutaneously administered at same dose of 100 ㎍/㎏. Both groups did not show any change in body weights and food consumption for 4 weeks compared with those of pretreatment. Both groups did not show any change in total leukocyte count (WBC) and platelet count, while both groups showed increased platelet distribution width (PDW) percentage in HM10760 group during a period from day 5 to day 59 and in Aranesp<SUP>®</SUP> group during a period from day 9 to day 26. Both groups showed increases in red blood cells (RBC), hemoglobin (HGB), and hematocrit (HCT) approximately 10 days after treatment compared with those of pretreatment (day 0). The increased levels of RBC, HGB, and HCT were much higher in HM10760 than in Aranesp<SUP>®</SUP> by the increases of 3.2%~ 12.5% for RBC, 3.8%~17.1% for HCT, and 1.85%~11% for HGB. Both groups showed increases in red cells distribution width (RDW) and reticulocyte (RET) compared with those of pretreatment, showing the highest peak from day 9. The increased level of RET lasted up to day 14 in Aranesp<SUP>®</SUP> group, while it lasted up to day 23 in HM10760 group. The increased level of RDW lasted up to day 59, it was much higher in HM10760 by the increase of 10.1%~17.6% than in Aranesp<SUP>®</SUP> group. In serum biochemistry, both groups showed a decrease in chloride level compared with those of pretreatment. These findings indicated that HM10760 increased RBC, HGB, HCT, RDW, and RET compared with those of pretreatment, and the increased levels were much higher in HM10760 than in Aranesp<SUP>®</SUP>.

영장류의 사육관리 및 독성평가

Kim Choong-Yong(김충용) 한국실험동물학회 2003 한국실험동물학회 학술발표대회 논문집 Vol.2003 No.-

GLP와 안전성평가

Choong-Yong Kim(김충용) 한국실험동물학회 2008 한국실험동물학회 학술발표대회 논문집 Vol.2008 No.-

LC/MS/MS를 이용한 원숭이 및 비글견의 간 및 장관 조직에서의 Doxifluridine과 대사체 5-FU 동시분석법 개발

우영아,김기환,정은주,김충용,Woo, Young-Ah,Kim, Ghee-Hwan,Jeong, Eun-Ju,Kim, Choong-Yong 대한약학회 2008 약학회지 Vol.52 No.2

A liquid chromatographic method with tandom spectrometric detection (LC/MS/MS) for the simultaneous determination of doxifluridine and its active metabolite, 5-fluorouracil (5-FU) was developed over the concentration range of $5{\sim}2000$ ng/ml, respectively. Doxifluridine, 5-FU and internal standard, 5-chlorouracil (5-CU), were extracted from liver and intestine tissue via protein precipitation. Acetonitrile was used as the extraction solvent and the supernatant was evaporated and reconstructed in mobile phase. Optimum chromatographic separation was achieved on a Agilent Zorbax $C_{18}$ ($100\;mm{\times}2.1\;mm$, $3.5\;{\mu}m$) column with mobile phase run in isocratic with methanol : water (20 : 80, v/v). The flow rate was 0.2 ml/min with total cycle time of 5 min. The lower limit of quantification was validated at 5.0 ng/ml of liver and intestine tissue, for both doxifluridine and 5-FU, respectively. The intra-day and inter-day precision and accuracy of quality control (QC) samples were <11% coefficient of variation and <7% relative error from theoretical concentration for both analytes. In addition, the special designed stability study was performed, because the metabolism of doxifluridine occurs spontaneously even in ice bath for monkey liver. The stability of doxifluridine in liver and intestine of monkey and beagle dog was compared. It was found that bioanalytical validation could not be performed for the monkey liver; however, beagle dog's liver has relatively low speed of metabolism compared to monkey liver and instead of monkey liver, beagle dog's liver could be used for the validation. Bioanalytical validation could be performed in monkey intestine. Eventually, this developed method for liver and intestine will be useful in support of the toxicokinetic and pharmacokinetic studies of doxifluridine and 5-FU.