Toxic effects of triptolide on adrenal steroidogenesis in H295R cells and female rats

Abstract

Triptolide (TP), a major active ingredient of Tripterygium wilfordii, exerts potent immunosuppressive effects in the treatment of rheumatoid arthritis but is not widely used in clinical practice due to its multiorgan toxicity, particularly hepatotoxicity, nephrotoxicity, and reproductive toxicity. An LC-MS/MS approach was employed to explore the endocrine-disrupting effects of TP. The endocrine-disrupting effects of various concentrations (0-100 nM) of TP for 48 hour were firstly investigated using an in vitro model (H295R cell line). It was found that TP did not decrease cell viability.The transcriptional levels of steroidogenic enzymes in H295R cells were assessed by quantificational real-time polymerase chain reaction. The possible adrenal and endocrine effects of oral administration of TP (0, 50, and 500 μg/kg) for 28 days on both normal and collagen-induced arthritis (CIA) rats were also explored. The serum and adrenal tissue hormone levels (corticosterone and progesterone) and adrenal histopathology were analyzed, with the results that TP significantly decreased the level of cortisol in H295R cells and the level of plasma corticosterone in both normal and CIA rats. Histological alterations in adrenal cortex were observed at the dose of 500 μg/kg. Exposure to TP for 48 hour had an obvious inhibitory effect on the messenger RNA transcript levels of HSD3B2, CYP21A2, CYP17A1, and CYP11B1, which is essential for the synthesis of corticosteroids. In a word, TP leads to the disorder of corticosteroid synthesis and secretion, and corticosteroid may be a potential biomarker for the treatment of multiorgan toxicity of TP.

Protective role of autophagy in triptolide-induced apoptosis of TM3 Leydig cells

“…[ 40 ] TP is observed on the inhibition of the mRNA expression of most genes related to steroigenesis. [ 41 , 42 ] All that provide new views into the impact of steroidogenesis on the severe reproductive toxicity of TP. The steroidal toxicity of TP might be mainly due to disruption of direct cytotoxicity, which would lead to reduced sex steroid synthesis and reproductive dysfunction.…”

Ginsenoside Rb1 Attenuates Triptolide-Induced Cytotoxicity in HL-7702 Cells via the Activation of Keap1/Nrf2/ARE Pathway

“…Fas is an important death receptor that mediates apoptosis. The interaction between Fas and its ligand FasL activates caspase-8, thereby triggering activation of downstream effector caspase-3, and ultimately initiating apoptosis (Zhou et al, 2017b;Xu et al, 2019b;You et al, 2019). Another major pathway for regulation of apoptosis is the mitochondrial-dependent intrinsic apoptosis pathway.…”

“…These properties account for its wide application in the treatment of systemic lupus erythematosus, rheumatoid arthritis, central nervous system diseases, and nephrotic syndrome ( Li et al, 2014 ). However, the clinical application of TP is hampered by its toxic effects on multiple cells and organs: it has been associated with nephrotoxicity, hepatotoxicity, cardiotoxicity, and reproductive toxicity ( Ruan et al, 2017 ; You et al, 2018 ; Wang et al, 2019a ; Xu et al, 2019b ). The hepatotoxicity of TP is of widely concern since it may cause liver damage in animals and humans ( Zhou et al, 2017a ).…”

Peer Review #1 of "The reproductive inhibitory effects of levonorgestrel, quinestrol, and EP-1 in Brandt’s vole (Lasiopodomys brandtii) (v0.1)"

“…Although fertility control agents, such as oestrogen and triptolide, can cause temporary infertility in animals, they can be toxic (Kejuan et al 2007;Lipschutz et al 1966;Maier & Herman 2001;van Aerts et al 2019;Xu et al 2019;Yuan et al 2019) and can cause death at higher dosages (Lehmann et al 1989;Zhang et al 2015;Zhang 2015). Therefore, it is important to estimate the toxicity in animals prior to using fertility control agents (Ettlin & Prentice 2002;Gao & Short 1993;Ratti et al 2015;Turner et al 2011;Zhang et al 2015).…”