Altered Gene Expression of Cytochrome P450 and ABC Transporter in Human Hepatocellular Carcinoma HepG2 Cells Exposed to Bardoxolone Methyl.

Bardoxolone methyl (BX) is expected to be an innovate therapeutic agent for chronic kidney disease (CKD). The aim of the present study was to examine whether the expression of subtypes of cytochrome P450 (CYP) and ABC transporters was altered in human hepatocellular carcinoma HepG2 cells by exposure to BX. The expression of mRNAs for CYP1A2, CYP2E1, P-glycoprotein, multidrug resistance-associated protein 1-3, and breast cancer resistance protein was significantly increased by exposure of HepG2 cells to BX, while the expression of CYP3A4 mRNA was significantly decreased under the same conditions. BX had no significant effect on the expression of mRNAs for CYP2C9 and CYP2C19 in HepG2 cells. In conclusion, this study demonstrated that the gene expression of several CYPs and ABC transporters in HepG2 cells was altered when exposed to BX, suggesting the need to pay careful attention to drug-drug interactions in patients receiving BX for CKD treatment.

A phase III, multicenter, single-arm study to assess the utility of indocyanine green fluorescent lymphography in the treatment of secondary lymphedema.

OBJECTIVE: Indocyanine green (ICG) fluorescent lymphography might be useful for assessing patients undergoing lymphatic surgery for secondary lymphedema. The present clinical trial aimed to confirm whether ICG fluorescent lymphography would be useful in evaluating lymphedema, identifying lymphatic vessels suitable for anastomosis, and confirming patency of lymphaticovenular anastomosis in patients with secondary lymphedema. METHODS: The present phase III, multicenter, single-arm, open-label, clinical trial (HAMAMATSU-ICG study) investigated the accuracy of lymphedema diagnosis via ICG fluorescent lymphography compared with lymphoscintigraphy, rate of identification of lymphatic vessels at the incision site, and efficacy for confirming patency of lymphaticovenular anastomosis. The external diameter of the identified lymphatic vessels and the distance from the skin surface to the lymphatic vessels using preoperative ICG fluorescent lymphography were measured intraoperatively under surgical microscopy. RESULTS: When the clinical decision for surgery at each research site was made, the standard diagnosis of lymphedema was considered correct. For the 26 upper extremities, a central judgment committee who was unaware of the clinical presentation confirmed the imaging diagnosis was accurate for 100.0% of cases, whether the assessments had been performed via lymphoscintigraphy or ICG lymphography. In contrast, for the 88 lower extremities, the accuracy of the diagnosis compared with the diagnosis by the central judgment committee was 70.5% and 88.2% for lymphoscintigraphy and ICG lymphography, respectively. The external diameter of the identified lymphatic vessels was significantly greater in the lower extremities than in the upper extremities (0.54 ± 0.21 mm vs 0.42 ± 0.14 mm; P < .0001). Also, the distance from the skin surface to the lymphatic vessels was significantly longer in the lower extremities than in the upper extremities (5.8 ± 3.5 mm vs 4.4 ± 2.6 mm; P = .01). For 263 skin incisions, with the site placement determined using ICG fluorescent lymphography, the rate of identification of lymphatics vessels suitable for anastomosis was 97.7% (95% confidence interval, 95.1%-99.2%). A total of 267 lymphaticovenular anastomoses were performed. ICG fluorescent lymphography was judged as "useful" for confirming patency after the anastomosis in 95.1% of the cases. CONCLUSIONS: ICG fluorescent lymphography could be useful for improving the treatment of patients with secondary lymphedema from the outpatient setting to surgery.