Effect of Thalidomide on Endotoxin-Induced Decreases in Activity and Expression of Hepatic Cytochrome P450 3A2

Abstract

Inflammatory cytokines induced by endotoxin, which is an active component in the outer membrane of gram-negative bacteria, are known to induce damages in numerous organs including the liver. The liver plays a pivotal role for the detoxification and elimination of endogenous and exogenous toxic compounds. Other investigators and we have reported that endotoxin and/or endotoxin-induced inflammatory mediators reduce hepatic drug-metabolizing enzyme activity by reducing the cytochrome P450 (CYP) activity and expression of the mRNA and protein. [1][2][3][4][5] Minamiyama and colleagues 1) have reported that the overproduction of nitric oxide (NO) in plasma by endotoxin directly inactivates hepatic CYP activities. Moreover, Hara and Adachi 6) have reported that NO down-regulates CYP gene expression by directly inhibiting hepatic nuclear factor-4 (HNF4), which is an important factor for constitutive expression of CYP. These findings suggest that NO plays an important role in the decreased hepatic CYP activity and/or protein in endotoxemia.There are a number of reports suggesting that inflammatory cytokines, including tumor necrosis factor-alpha (TNFa), interleukin-1b (IL-1b), IL-6 and interferon, might play an important role in the down-regulation of hepatic CYP isoforms induced by endotoxin.3,7-9) Additionally, it is proposed that one possible mechanism of the down-regulation of CYP isoforms induced by endotoxin is closely associated with the repression of nuclear hormone receptors constitutive androstane receptor (CAR), pregnane X receptor (PXR) and peroxisome proliferator-activated receptor-g (PPAR-g), which are the key regulators of some CYP subtype gene expressions in the liver. 4,10) It has recently been found that thalidomide, initially used as a sedative and hypnotic, has anti-inflammatory, immunomodulatory, and anti-angiogenic effects.11,12) Therefore, it is newly used in the treatment of various diseases, including multiple myeloma, cancer, and others. [13][14][15][16] Although the mechanism responsible for clinical efficacy of thalidomide is still not clear, several investigators have suggested the possible involvement of selective inhibition of TNF-a production. [17][18][19][20][21] There are interesting reports suggesting that thalidomide improves endotoxin-or alcohol-induced liver injury, 22,23) and prolongs the survival rate following the experimental sepsis induced by endotoxin or bacterial challenge in rats. 24,25) Shimazawa et al. 26) have reported that thalidomide and its analogs have NO synthase (NOS)-inhibitory activity in vitro, but the activity of thalidomide is weak. Enomoto et al. 27) reported that thalidomide abolishes the endotoxin-induced increase in CD14 expression in Kupffer cells in vitro. To our knowledge, the effect of thalidomide on the reduction in hepatic function in endotoxemia has not yet been elucidated.The purpose of the present study was to investigate the effect of thalidomide on endotoxin-induced decreases in hepatic function, particularly CYP-mediated drug-metabolizing ...

Thalidomide Attenuates Airway Hyperresponsiveness and Eosinophilic Inflammation in a Murine Model of Allergic Asthma

“…The U.S.A. Food and Drug Administration approved it for this indication in 1998. 3) Thalidomide, which is metabolized by cytochrome P450, 3,4) has a wide range of pharmaceutical and biological activities. Currently, clinical investigations of thalidomide have been conducted in patients with diverse diseases, including multiple myeloma, rheumatoid arthritis, and human immunodeficiency virus infection.…”