Osthole prevents tamoxifen-induced liver injury in mice

Abstract

Tamoxifen (TMX) is an antiestrogen drug that is used in the treatment and prevention of all stages of estrogen-dependent breast cancer. Adverse effects of TMX include hepatotoxicity. In this study, we investigated the therapeutic effects of osthole, isolated from medicinal plants especially Fructus Cnidii, on TMX-induced acute liver injury in mice. Mice were injected with osthole (100 mg/kg, ip) or vehicle, followed by TMX (90 mg/kg, ip) 24 h later. We showed that a single injection of TMX-induced liver injury and oxidative stress. Pretreatment with osthole attenuated TMX-induced liver injury evidenced by dose-dependent reduction of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Pretreatment with osthole also blunted TMX-induced oxidative stress, evidenced by significant increase of reduced glutathione (GSH) as well as reduction of malondialdehyde (MDA) and hydrogen peroxide (H 2 O 2). Consistently, osthole significantly enhanced the expressions of antioxidant genes (GPX1, SOD2, GCL-c, and G6pdh), but suppressed those of pro-oxidant genes (NOX2 and ACOX). Furthermore, osthole inhibited the production of inflammatory cytokines, reduced the metabolic activation of TMX, and promoted its clearance. We further revealed that osthole elevated hepatic cAMP and cGMP levels, but inhibition of PKA or PKG failed to abolish the hepatoprotective effect of osthole. Meanwhile, prominent phosphorylation of p38 was observed in liver in response to TMX, which was significantly inhibited by osthole. Pretreatment with SB203580, a p38 inhibitor, significantly attenuated TMX-induced increase of ALT and AST activities, reduced oxidative stress, and reversed the alterations of gene expression caused by TMX. Moreover, pretreatment with L-buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, partly reversed the effect of osthole on TMX-induced liver injury. Consistently, pretreatment with N-acetyl-L-cysteine (NAC) significantly attenuated TMX-induced increase in ALT and AST activities. Notably, both BSO and NAC had no detectable effect on the phosphorylation levels of p38. Collectively, our results suggest that osthole prevents TMX hepatotoxicity by suppressing p38 activation and subsequently reducing TMX-induced oxidative damage.

Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway

“…Osthole exhibited various pharmacological activities, including antioxidant [229][230][231], anticancer [232,233], and antiinflammatory properties [231,234,235].…”

An Approach to Enhance Dissolution Rate of Tamoxifen Citrate

“…The typical dose for tamoxifen treatment is between 20 and 40 mg daily for 5 years [3]. Unfortunately, this prolonged period of treatment and accumulation does present an increased probability of hepatotoxicity and endometrial cancer due to its long half-life of 5–7 days [3–5]. Furthermore, the bioavailability of TC has been previously reported to be in the range of 20–30% [6].…”

Phytochemistry, Ethnopharmacology, Pharmacokinetics and Toxicology of Cnidium monnieri (L.) Cusson

“…Another mechanism is that osthole (100 mg/kg) could dramatically inhibit the mRNA levels of cytokines including TNF-α, IL-1β, IL-6, and MCP-1, additionally, it could down-regulate the gene expressions of the CYP2D6, CYP2E1, CTP3A11, and CYP4A10 while up-regulating the gene expressions of UGT1A1, UGT1A6, UGT2B1, SULT2A1, and GSTM. It also exerted the hepaprotective effect by reducing p38 phosphorylation and exerted antioxidative effects [228]. Osthole (10 mg/kg) decreased the liver production of α-smooth muscle actin (α-SMA), inflammatory cytokines and chemokines in thioacetamide treated rats.…”

“…In vitro [204] Anti-cancer effect Osthole 0, 20, 40, 60, 80, 100, 200 µmol/L for 24 and 48 h In vitro [205] Anti-cancer effect Osthole 20 µmol/L In vitro [206] Anti-cancer effect Osthole 0, 25, 50, and 100 µmol/L In vitro [207] Anti-cancer effect Osthole 0, 20, 40, 60, 80, and 100 µmol/L In vitro [208] Anti-cancer effect Osthole 20 µmol/L In vitro [209] Anti-cancer effect Osthole 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 µg/mL In vitro [210] Anti-cancer effect Osthole 50 µmol/L In vitro [211] Anti-cancer effect Osthole 0, 30, 60, 90, and 120 µmol/L In vitro [212] Anti-cancer effect Osthole 1.5 µg/(g•10 µL) every other day for 7 times via abdominal injection In vivo+ In vitro [213] Anti-cancer effect Osthole 0, 20, 40, and 80 µg/mL In vitro [214] Anti-cancer effect Osthole 20, 40, 80, 120, 160, and 200 µmol/L In vitro [215] Anti-cancer effect Osthole 10 µg/mL In vitro [216] Anti-cancer effect Osthole 0, 50, 100, and 200 µM In vitro [227] Anti-cancer effect Osthole 1, 10, and 30 µM In vitro [228] Anti-cancer effect Osthole 100 mg/kg via intraperitoneal administration In vivo [229] Anti-cancer effect Osthole 0, 50, 100, and 150 µM In vitro [230] Anti-hepatotoxicity effect Osthole 10 mg/kg via gavage twice per day for 4 weeks, 1, 3, and 10 µg/mL In vivo+ In vitro [231] Anti-cardiotoxicity effect Osthole 5, 10, and 20 mg/kg per day for 16 days via intraperitoneal administration In vivo [232] Anti-neurotoxicity effect Osthole 0.01, 0.05, 0.1 mmol/L In vitro [233] Anti-idiopathic pulmonary fibrosis Osthole 1, 10, and 50 µmol/L In vivo [234] Anti-focal segmental glomerulosclerosis effect Osthole 30 mg/kg per day for 7 days and 28 days via intraperitoneal injection In vivo [235]…”