[Metabolic detoxification of bakuchiol is mediated by cytochrome P450 enzymes in human liver microsomes].

OBJECTIVE: To analyze cytochrome P450 (CYP) phenotyping for bakuchiol metabolism and study the mechanism of detoxification of bakuchiol by human liver microsomes (HLM) in vitro. METHODS: The CYP phenotyping for bakuchiol metabolism was determined using HLM combined with CYP specific inhibitors and recombinant human CYP isoforms. The relative activities of CYP isoforms were determined by analyzing the formation of the substrate metabolites using HPLC-MS/MS, in presence or absence of 1-aminobenzotriazole (ABT) which was CYP enzymes' broad spectrum inhibitor. The residual concentrations of bakuchiol in microsomal incubates were determined using HPLC to investigate ABT's effect on the metabolism of bakuchiol. The effects of CYP enzymes on the nephrotoxicity of bakuchiol were investigated using human kidney-2(HK-2) by MTT assay, in presence or absence of ABT. RESULTS: CYP1A2, CYP2C9, CYP2C19 and CYP3A4 in HLM were involved in bakuchiol metabolism, among which CYP2C19 showed the highest metabolic rate. Co-incubation with ABT (2.5 mmol/L) could inhibit more than 90% of the enzyme activities for CYP1A2, CYP2C9, CYP2C19 and CYP3A4. ABT (2.5 mmol/L) could inhibit the HLM metabolism of bakuchiol with inhibition ratio 83.24%±2.13%. When preincubated with ABT, the metabolic detoxification of bakuchiol by HLM was significantly reduced (P<0.05). CONCLUSION: The mechanism of metabolic detoxification of bakuchiol by HLM is associated with bakuchiol metabolism by CYP enzymes to form non toxic or lower toxic metabolites. The broad spectrum inhibitor of CYP could inverse the detoxification of HLM.

Domestic trends in malaria research and development in China and its global influence.

BACKGROUND: Though many countries, including China, are moving towards malaria elimination, malaria remains a major global health threat. Due to the spread of antimalarial drug resistance and the need for innovative medical products during the elimination phase, further research and development (R&D) of innovative tools in both epidemic and elimination areas is needed. This study aims to identify the trends and gaps in malaria R&D in China, and aims to offer suggestions on how China can be more effectively involved in global malaria R&D. METHODS: Quantitative analysis was carried out by collecting data on Chinese malaria-related research programmes between 1985 and 2014, invention patents in China from 1985 to 2014, and articles published by Chinese researchers in PubMed and Chinese databases from 2005 to 2014. All data were screened and extracted for numerical analysis and were categorized into basic sciences, drug/drug resistance, immunology/vaccines, or diagnostics/detection for chronological and subgroup comparisons. RESULTS: The number of malaria R&D activities have shown a trend of increase during the past 30 years, however these activities have fluctuated within the past few years. During the past 10 years, R&D on drug/drug resistance accounted for the highest percentages of research programmes (32.4%), articles (55.0% in PubMed and 50.6% in Chinese databases) and patents (45.5%). However, these R&D activities were mainly related to artemisinin. R&D on immunology/vaccines has been a continuous interest for China's public entities, but the focus remains on basic science. R&D in the area of high-efficiency diagnostics has been rarely seen or reported in China. CONCLUSIONS: China has long been devoted to malaria R&D in multiple areas, including drugs, drug resistance, immunology and vaccines. R&D on diagnostics has received significantly less attention, however, it should also be an area where China can make a contribution. More focus on malaria R&D is needed, especially in the area of diagnostics, if China would like to contribute in a more significant way to global malaria control and elimination.