RESUMO
Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine catabolism that acts as a novel regulator of adipogenesis. In pathological states, xanthine oxidoreductase activity increases to produce excess reactive oxygen species (ROS). The nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical inducer of antioxidants, which is bound and repressed by a kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. The Keap1-Nrf2 axis appears to be a major mechanism for robust inducible antioxidant defenses. Here, we demonstrate that febuxostat, a xanthine oxidase inhibitor, alleviates the increase in adipose tissue mass in obese mouse models with a high-fat diet or ovariectomy. Febuxostat disrupts in vitro adipocytic differentiation in adipogenic media. Adipocytes appeared at day 7 in absence or presence of febuxostat were 160.8 ± 21.2 vs. 52.5 ± 12.7 (p < 0.01) in 3T3−L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (p < 0.01) in 10T1/2 cells, respectively. Adipocyte differentiation was further enhanced by the addition of hydrogen peroxide, which was also suppressed by febuxostat. Interestingly, febuxostat, but not allopurinol (another xanthine oxidase inhibitor), rapidly induced the nuclear translocation of Nrf2 and facilitated the degradation of Keap1, similar to the electrophilic Nrf2 activator omaveloxolone. These results suggest that febuxostat alleviates adipogenesis under oxidative conditions, at least in part by suppressing ROS production and Nrf2 activation. Regulation of adipocytic differentiation by febuxostat is expected to inhibit obesity due to menopause or overeating.
RESUMO
Interleukin 6 (IL-6) plays a central role in the immunopathogenesis of rheumatoid arthritis (RA) and tocilizumab [TCZ] (an anti-IL-6 receptor antibody) has been shown to be effective in the treatment of the condition. As up-regulation of IL-6 reduces the activity of cytochrome P450 (CYP) enzymes, blockade of this cytokine may enhance CYP function. This may lead to reduced bioavailability of CYP-metabolized drugs. Due to the increasing use of TCZ, we undertook a systematic literature review to explore such interactions. Our search was conducted in MEDLINE, EMBASE, Web of Science, FDA and EMEA websites for in vitro and in vivo studies, clinical trials and reviews mentioning TCZ and CYP on the basis of the title and abstract. Appropriate articles were further screened based on full-text review to select only those reporting IL-6, TCZ and their potential interaction with CYP-metabolized drugs. Two in vitro studies showed that TCZ-reversed IL-6 induced reduction of CYP isozymes. CYP3A4 mRNA expression was most reduced by IL-6 followed by CYP2C9 and CYP2C19. This change was prevented with TCZ. Three clinical studies investigated the interaction showing simvastatin (CYP3A4 substrate) bioavailability reduced by TCZ and omeprazole bioavailability was decreased by TCZ-induced CYP2C19 activity. The bioavailability of dextromethorphan (CYP2D6 and CYP3A4 substrates) was shown to be unaffected by TCZ treatment. The observed increase in CYP isozyme activity by TCZ is of clinical relevance as the bioavailability of the CYP isozyme substrates were decreased in vivo. As CYP3A4 is the isozyme responsible for the largest proportion of drug metabolism, it is probable that the bioavailability of other drugs may be reduced by TCZ. Thus, clinicians should exercise caution when co-prescribing TCZ and CYP-metabolized drugs. More studies are required to investigate this interaction further.