편평상피세포암 세포주 AMC-HN-6의 Retinoids 대사에 all-Trans-rectionic Acid Structural Analog인 Sorbic Acid가 미치는 영향

한인석 ( In Seok Han ),김상윤 ( Sang Yoon Kim ),문기찬 ( Kee Chan Moon ),성경재 ( Kyung Jeh Sung ),최지호 ( Jee Ho Choi ),고재경 ( Jai Kyoung Koh ),정의창 ( Eui Chang Chung ) 대한피부과학회 1999 대한피부과학회지 Vol.37 No.8

Retinoids는 피부과 질환인 건선, 여드름, 피부노화, 주름살제거 등의 치료에 사용되는 이외에도 급성 전골수구성 백혈병(acute promyelocytic leukemia)의 치료제, 두경부암의 치료 후 발생하는 이차 원발암의 방지 및 암의 전구질환인 백판증(leukoplakia)이 암으로 진행되는 것을 억제하는 등 악성종양의 치료제로도 이용되고 있다. Retinoids의 치료 효과를 얻기 위해서는 retinoids를 세포내에서 일정한 농도 이상으로 장기간 유지하는 것이 필요한데 retinoids를 투여하면 이를 대사시키는 효소가 유도되고 그 결과로 retinoic acid가 매우 빨리 대사되어 비활성화되는 문제점이 있다. 세포내 all-trans retinoic acid(ATRA) 농도를 결정하는 기전은 세포에 의한 all-trans retinoic acid(CRABP)의 발현정도, cytochrome P450을 포함한 all-trans retinoic acid 대사에 관여하는 효소들의 활성도 등 여러 가지 요소들이 관여하고 있다. All-trans retinoic acid에 의해서 발현이 유도되는 all-trans retinoic acid specific cytochrome P450은 all-trans retinoic acid의 대사에 관여하는 가장 중요한 효소중의 하나로 all-trans retinoic acid를 all-trans-4-hydroxy-retinoic acid(4-OH-RA), all-trans -18-hydroxy-retinoic acid(18-OH-RA) 및 all-trans-4-oxo-retinoic acid(4-OXO-RA) 등 극성대사산물(polar metabolites)로 대사시킴으로써 all-trans retinoic acid의 세포내 농도를 저하시키고 그 결과로 all-trans retinoic acid의 생물학적 효과를 감소시켜서 임상적 사용에 장애요인으로 작용한다. 따라서 all-trans retinoic acid specific cytochrome P450을 선택적으로 억제하는 약제의 개발은 all-trans retinoic acid의 임상적 효과를 유지하거나 강화하는데 필요하며 세포내 내인성 all-trans retinoic acid의 농도를 증가시켜줌으로써 all-trans retinoic acid의 투여에서 오는 부작용들도 감소시켜줄 수 있으므로 최근에 많은 연구가 이루어지고 있다. 최근에 liarozole과 ketoconazole이 세포내 all-trans retinoic acid 대사에 관여하는 cytochrome P450을 억제한다는 것이 밝혀졌으며 두 약제를 실험동물에 투여하면 all-trans retinoic acid 투여 없이도 혈중 all-trans retinoic acid 농도를 증가시킨다는 보고도 있다. 저자들은 이전의 연구결과를 통해서 all-trans retinoic acid 분자의 꼬리부분(carboxyl-terminus)은 정전기적힘(electrostatic force)에 의해 all-trans retinoic acid specific cytochrome P450의 특정 부위에 결합하며 all-trans retinoic acid 분자의 머리부분(β-cyclogeramylidene ring)은 소수성 결합력(hydrophobic force)에 의해서 cytochrome P450의 활성 부위에 결합할 가능성을 이미 보고한 바 있다. 이에 따라 두경부 편평상피세포암 환자들에서 만든 8개의 AMC-HN 편평상피세포암 세포주들 중에서 all-trans retinoic acid에 의해서 P450이 현저하게 유도되는 AMC-HN-6 편평상피세포암 세포주를 이용해서 all-trans retinoic acid 분자의 꼬리부분과 구조적으로 유사한 sorbic acid(Fig. 1)가 all-trans retinoic acid specific cytochrome P450에 결합되어 all-trans retinoic acid의 대사에 어떠한 영향을 미치는가를 알아보기 위해서 본 연구를 시행하였다. Background:All-trans-retinoic acid metabolism by cytochrome P450 is one of the major mechanisms that can regulate the level of retinoids in cells. Therefore, enhanced metabolism of all-trans retinoic acid by all-trans retinoic acid induced cytochrome P450 would probably decrease the therapeutic effects of active retinoids. We previously reported that the tail of all-trans retinoic acid(the carboxyl-terminus) may bind to a binding site of cytochrome P450 in part by electrostatic forces, and the head of RA(the β-cyclogeranylidene ring) may bind to an active site of cytochrome P450 in part by hydrophobic forces. It is very interesting to study the interactions between the RA binding site of cytochrome P50 induced by all-trans retinoic acid and the structural analogs of all-trans retinoic acid and its effects of RA metabolism. Objective:The purpose of this study is to examine the effects of sorbic acid, that has a similar structure with the tail of all-trans retinoic acid, on RA metabolism in head-neck squamous cell carcinoma cell line AMC-HN-6 which showed a much increased induction of cytochrome P450 by all-trans retinoic acid. Methods:We examined the effects of sorbic acid on RA metabolism in all-trans retinoic acid specific cytochrome P450-inducible AMC-HN-6 cell line using cytochrome P450 enzyme assay with acid were separated by thin layer chromatography and the radioactivity was measured by β-counter. Metabolic activity was expressed as the percentage of total radioactivity of polar metabolites. Results:The results are summurized as follows: 1. RA metabolism of AMC-HN-6 cell line was inhibited by actinomycin D and cyclohexamide and was also inhibited by ketoconazole, the cytochrome P450 inhibitor, in a concentration-dependent manner. 2. Cytochrome P450-mediated oxidation was induced by all-trans retinoic acid, 13-cis-RA, 9-cis-RA, and retinal, but not by retinol in AMC-HN-6 cell line. 3. Sorbic acid inhibited RA metabolism of AMC-HN-6 cell line in a concentration-dependent manner when the enzyme assay was performed on microsomal protein but could not inhibit RA metabolism in total cell lysate enzyme assay. Conclusion:The conversion of all-trans retinoic acid to polar metabolites is inhibited by sorbic acid in microsomal enzyme assay of AMC-HN-6 cell line, but not in total cell assay. These results suggest that sorbic acid can bind to the active binding site of cytochrome P450 but binding affinity of sorbic acid to RA binding molecules such as CRABP-Ⅰ,-Ⅱ, RARs, RXRs may be stronger than that of sorbic acid to cytochrome P450.(Korean J Dermatol 1999;37(8):992∼1000)

윤상 육아종의 임상 및 병리조직학적 고찰

임연순(Yeon Soon Lim),장경애(Kyoung Ae Jang),이미우(Mi Woo Lee),최지호(Jee Ho Choi),성경재(Kyung Jeh Sung),문기찬(Kee Chan Moon),고재경(Jai Kyoung Koh) 대한피부과학회 1999 대한피부과학회지 Vol.37 No.8

윤상 육아종은 원인 미상의 양성 피부질환으로서 임상및 병리조직학으로 전형적인 형태와 비전형적인 다양한 형태가 존재하고, 주로 신체의 말단 부위에 구진이나 판으로 나타나며 윤상의 형태를 보이는 경우가 많다. 여자에서의 발생율이 2~3배정도 높으며 모든 나이에 발생할수 있으나 어린아이나 젊은 성인에서 주로 발생한다. 발생기전은 면역기전이 관여할 것으로 생각되며 그중 세포매개성 면역이 주된 작용을 할 것이라고 생각되나 아직까지 정확한 기전은 정립되어 있지 않은 상태이다. 후천성 면역결핍증의 발생과 장기이식 등의 증가로 인한 면역결핍상태에서 윤상 육아종의 보고가 증가되고 있으며, 이로 인해 면역학적 발생기전의 연구에 더욱 관심이 모아지고 있다. 저자들은 1990년 1월부터 1998년 9월까지 서울 중앙병원 피부과에서 임상 및 병리조직검사 결과 윤상 육아종으로 진단받은 38명의 환자를 대상으로 임상과 병리조직학적 검색을 실시하였다. Background:Granuloma annulare(GA) is a benign skin disorder of unknoun etiology. Even though some cases were reported in Korean journals, systematic reviews of clinical and histopathologic features of granuloma annulare were not dene. Objective:The purpose of this study was to analyze the clinical and histological charcateristics of granuloma annulare. Methods:In a retrospective study including 38 patients and 44 skin biopsy specimens, we reviewed the clinical and histological features of granuloma annulare. Results:The results were as follows; 1. The ratio of female-to-male patients was 4.4:1 and in the majority of cases(68.4%), the onset of GA occured in the first three decades of life and the mean age of onset was 22.7 years. In the majority of cases(65.8%), the duration was less than 6 months and the mean duration was 22 months. 2. The clinical types were localized type(52.6%), subcutaneous type(26.3%), and generalized type(21.1%). 3. The lower extremities(42.9%), especially the knee joint was the most common anatomic site. 4. Ten patients(26.3%) have systemic diseases including diabetes mellitus(10.5%), thyroid disease, SLE, anemia, osteoarthritis, atopic dermatitis, and asthma. 5. Nine patients(23.7%) have precipitating factors including seasonal variation, insect bite, stress, and irritation of shoes and 15 patients(39.5%) have associated symptomes including an itching sensation and pain or tenderness. 6. The histological findings were as follows;The histologic types were dermal granuloma(50%) and subcutaneous type(50%). The dermal granulomatous lesions consist of interstitial type(11 cases, 25.0%), palisading type(8 cases, 18.2%), perforating type(2 cases, 4.5%), and epithelioid tubercle type(1 case, 2.3%). Mucin deposition was detected in the 88.6%, eosinophils in 31.8%, and neutrophils in 13.6%. Conclusion:Granuloma annulare has various clinical and histological variants, and some cases are associated with systemic diseases. And we need to have an interest because recently granuloma annulares developed in immunocompromised patients, such as AIDS and bone marrow transplants.(Korean J Dermatol 1999;37(8):1001~1008)

Primary Cutaneous CD30 ( Ki - 1 ) - Positive Pleomorphic Large Cell Lymphoma in a Patient with Generalized Lichen Myxedematosus

정승태,문기찬,성경재,고재경,지도현,최재호 대한피부과학회 1997 Annals of Dermatology Vol.9 No.1

A case of primary cutaneous CD30(Ki-1)-positive pleomorphic large cell lymphoma in a 51year-old woman with generalized lichen myxedematosus is presented. Histopathological findings of the biopsy specimens from the lichenoid papules of the left forearm and the dorsum of the right hand were compatible with papular mucinosis. The mucinous material in the papillary dermis stained with alcian blue at pH 2.5 and was susceptible to hyaluronidase, but serum protein electrophoresis showed no abnormal bands and an abnormal paraprotein was not detected in our patient. Histopathological examination of a solitary, firm, purplish nodule on the right popliteal area showed diffuse and extensive infiltration in the reticular dermis composed of large, atypical, often hyperchromatic, sometimes multinucleated and markedly pleomorphic cells. The majority of the large atypical cells were CD30(Ki-1) positive. The TCR gene rearrangement analysis demonstrated the presence of a monoclonal rearrangement of the Υ-TCR gene in the skin biopsy specimen of our patient. The organ-system survey revealed no evidence of internal organ involvement. We concluded that this was primary cutaneous CD30(Ki-1)-positive pleomorphic large cell lymphoma developing in a patient with generalized lichen myxedematosus.

Ribavirin ( Virazole ) 의 대상포진에 대한 치험

김광중,신용우,이유신,김원석,성경재,김홍석 대한피부과학회 1980 大韓皮膚科學會誌 Vol.18 No.6

Ribavirin(l-β-D-ribofuranosyl-l, 2, 4-triazole-3-carboximide, Virazole^R) is a. synthetic nucleoside derivative with reported broad spectrum activity in vitro and in vivo against a wide variety of DNA and RNA viruses. This drug works by selective inhibition of viral protein in the early stage of viral replication, but does not influence on host cell protein. The present study was undertaken to evaluate the therapeutic effect of Ribavirin in patients with herpes zoster. A total of 15 patients entered this study at the Department of Dermatology, Seoul National University Hospital during 5 months' period, from May, 1980 to September, 1980, Ribavirin(10mg/kg/d) was given to 10 patients. After initiation of therapy, we observed duration of pain and vesicles and onset of crust formation in each patient clinically. The results observed in the 15 patients were as follows. 1. The average duration of pain was 6. 0 days in Ribavirin group and 8. 6 days i@n. control group (p$lt;0. 05). 2. Postherpetic neuralgia was not @found in any patients treated with Ribavirin. 3. The average duzation of all vesicles and onset of crust formation were 7. 0 days and 3. 8 days in Ribavirin group and 7. 2 days and 4. 2 days in control group respectively. 4. No side effects were observed during the course of Ribavirin treatment.