학술논문
Increased Expression of P-glycoprotein in Human Macrophages: : a Potential Mechanism of Rifampin Induced Drug Resistance
Document Type
Dissertation/ Thesis
Author
Source
Subject
Language
English
Abstract
약물 내성 결핵 (drug resistant tuberculosis) 치료는 항결핵 약물 효능이 감소함에 따라 세계적인 문제로 대두되고 있다. 특히 항결핵 약물이 면역세포내의 약물efflux 수송체의 기질인 경우, 숙주 세포로 매개되는 결핵균 (Mycobacterium tuberculosis)의 약물 내성은 치료에 영향을 끼칠 수 있다. 본 연구는 THP1 macrophages 내의 MDR1 유전자 (P-glycoprotein) 발현에 rifampin (RIF)이 끼치는 영향을 평가하고자 한다. Phorbol 12-myristate 13-acetate (PMA)로 분화를 유도한 THP1 macrophages에 100 μM 농도의 RIF을 처리 한 경우, MDR1 유전자의 단백 및 mRNA 발현이 현저히 증가하였다 (각각p
Treatment of drug resistant tuberculosis (TB) is a global problem due to the reduced drug efficacy. The host cell mediated drug tolerance of Mycobacterium tuberculosis for anti-tuberculosis (anti-TB) drugs can affect the treatment success, especially when anti-TB drugs are substrate for the drug efflux transporter in immune cells. The present study was aimed to evaluate the effect of rifampin (RIF) on MDR1 gene (P-glycoprotein, P-gp) expression in THP1 macrophages. RIF at 100 µM concentration significantly induced the MDR1 gene at protein and mRNA levels in Phorbol 12-myristate 13-acetate (PMA) stimulated THP1 macrophages (P < 0.001 and 0.05, respectively). The pregnane X receptor (PXR) was found to be involved in the induction of P-gp protein expression in RIF treated THP1 macrophages. The PXR activation inhibitor resveratrol and ketoconazole significantly suppressed the RIF induced P-gp expression in THP1 macrophages (P < 0.05). RIF treated THP1 macrophages also exhibited a strong efflux of P-gp substrate, resulting in the reduced intracellular concentration of rhodamine-123 and the anti-TB drug prothionamide (P < 0.01 and 0.05, respectively). In contrast, the P-gp inhibitor cyclosporine A significantly increased intracellular accumulation of the rhodamine-123 and prothionamide (P < 0.001 and 0.05 respectively) in RIF treated THP1 macrophages. Additionally, the nuclear factor-kappa B (NF-κB) was found to be involved in P-gp expression regulation in RIF treated THP1 macrophages. The inhibition of NF-κB activation by celcoxib (25 µM) was found to be reduced the P-gp expression significantly (P
Treatment of drug resistant tuberculosis (TB) is a global problem due to the reduced drug efficacy. The host cell mediated drug tolerance of Mycobacterium tuberculosis for anti-tuberculosis (anti-TB) drugs can affect the treatment success, especially when anti-TB drugs are substrate for the drug efflux transporter in immune cells. The present study was aimed to evaluate the effect of rifampin (RIF) on MDR1 gene (P-glycoprotein, P-gp) expression in THP1 macrophages. RIF at 100 µM concentration significantly induced the MDR1 gene at protein and mRNA levels in Phorbol 12-myristate 13-acetate (PMA) stimulated THP1 macrophages (P < 0.001 and 0.05, respectively). The pregnane X receptor (PXR) was found to be involved in the induction of P-gp protein expression in RIF treated THP1 macrophages. The PXR activation inhibitor resveratrol and ketoconazole significantly suppressed the RIF induced P-gp expression in THP1 macrophages (P < 0.05). RIF treated THP1 macrophages also exhibited a strong efflux of P-gp substrate, resulting in the reduced intracellular concentration of rhodamine-123 and the anti-TB drug prothionamide (P < 0.01 and 0.05, respectively). In contrast, the P-gp inhibitor cyclosporine A significantly increased intracellular accumulation of the rhodamine-123 and prothionamide (P < 0.001 and 0.05 respectively) in RIF treated THP1 macrophages. Additionally, the nuclear factor-kappa B (NF-κB) was found to be involved in P-gp expression regulation in RIF treated THP1 macrophages. The inhibition of NF-κB activation by celcoxib (25 µM) was found to be reduced the P-gp expression significantly (P