Knockout of hepatic P450 reductase aggravates triptolide-induced toxicity

Xue, Xiang; Gong, Likun; Qi, Xinming; Wu, Yuanfeng; Xing, Guozhen; Yao, Jun; Luan, Yang; Xiao, Ying; Li, Yan; Wu, Xin; Chen, Min; Gu, Jun; Ren, Jin

doi:10.1016/j.toxlet.2011.05.003

Cited by 67 publications

(46 citation statements)

References 20 publications

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“…Fatty degeneration in the hepatocytes, dead cells in the macrophages manifested as a starry sky appearance in the spleen, and obvious kidney proximal tubular dilation were seen (Figure 11), which were also observed in male mice after oral administration of TP. 2 However, in the TP-NLCs group at the same dose, no apparent changes were found.…”

mentioning

confidence: 88%

“…25 In addition, previous literature reports indicate that TP could be metabolized by cytochrome P4503A in human and rat liver microsomes (with cytochrome P4503A4 as the primary isoform responsible for hydroxylation). 2,4 Thus, incorporation of TP in lipid nanoparticles might advantageously protect it from enzymatic degradation in the liver, resulting in reduced hepatic clearance, which was confirmed by reduced CLz/F and prolonged MRT and t 1/2z (Table 4). On the other hand, these changes in pharmacokinetic profile could also be attributable to cytochrome P4503A4 inhibition by Cremophor RH 40 45 and the fact that Compritol 888 ATO-based lipid nanoparticles were capable of going through lymphatic transport pathway and bypassing first-pass metabolism.…”

mentioning

confidence: 89%

“…8,9 Similarly, the reported T max and t 1/2 of TP in mice are 5.0 and 13.7 minutes, respectively. 2 These pharmacokinetic behaviors of TP indicate that it gains fast access into the blood circulation with a very short stay. This phenomenon can be explained by the combined effects of efficient gastrointestinal permeability, 6 rapid metabolism by cytochrome P4503A system in the liver, 4,10,11 and extensive tissue distribution.…”

Section: Introductionmentioning

confidence: 99%

“…This phenomenon can be explained by the combined effects of efficient gastrointestinal permeability, 6 rapid metabolism by cytochrome P4503A system in the liver, 4,10,11 and extensive tissue distribution. 2,9 The significant and rapid fluctuations of TP in plasma likely contribute to the toxicity of TP following oral administration. Therefore, a formulation with extended delivery potential and decreased fluctuations of plasma drug concentration is highly desirable for TP.…”

Section: Introductionmentioning

confidence: 99%

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Nanostructured lipid carriers as a novel oral delivery system for triptolide: induced changes in pharmacokinetics profile associated with reduced toxicity in male rats

Zhang¹,

Fan²,

Liu³

et al. 2014

IJN

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After oral administration in rodents, triptolide (TP), a diterpenoid triepoxide compound, active as anti-inflammatory, immunosuppressive, anti-fertility, anti-cystogenesis, and anticancer agent, is rapidly absorbed into the blood circulation (from 5.0 to 19.5 minutes after dosing, depending on the rodent species) followed by a short elimination half-life (from about 20 minutes to less than 1 hour). Such significant and rapid fluctuations of TP in plasma likely contribute to its toxicity, which is characterized by injury to hepatic, renal, digestive, reproductive, and hematological systems. With the aim of prolonging drug release and improving its safety, TP-loaded nanostructured lipid carriers (TP-NLCs), composed of Compritol® 888 ATO (solid lipid) and Capryol™ 90 (liquid lipid), were developed using a microemulsion technique. The formulated TP-NLCs were also characterized and in vitro release was evaluated using the dialysis bag diffusion technique. In addition, the pharmacokinetics and toxicology profiles of TP-NLCs were compared to free TP and TP-loaded solid lipid nanoparticles (TP-SLNs; containing Compritol 888 ATO only). Results demonstrate that TP-NLCs had mean particle size of 231.8 nm, increased drug encapsulation with a 71.6% efficiency, and stable drug incorporation for over 1-month. TP-NLCs manifested a better in vitro sustained-release pattern compared to TP-SLNs. Furthermore, TP-NLCs prolonged mean residence time (MRT) 0–t ( P <0.001, P <0.001), delayed T max ( P <0.01, P <0.05) and decreased C max ( P <0.01, P <0.05) compared to free TP and TP-SLNs, respectively, which was associated with reduced subacute toxicity in male rats. In conclusion, our data suggest that TP-NLCs are superior to TP-SLNs and could be a promising oral delivery system for a safer use of TP.

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confidence: 88%

mentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Nanostructured lipid carriers as a novel oral delivery system for triptolide: induced changes in pharmacokinetics profile associated with reduced toxicity in male rats

Zhang¹,

Fan²,

Liu³

et al. 2014

IJN

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“…66 Cytochrome P450 reductase enzyme also plays a significant role to eradicate triptolide induced toxicity. 67 …”

Section: Triptolide Induced Toxicitymentioning

confidence: 99%

Triptolide Mediated Amelioration of Breast Cancer via Modulation of Molecular Pathways

Sarkar

Paul

2017

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Triptolide is the main bioactive molecule isolated from a root extract of Tripterigium wilfordii Hook F. of Celastraceae family. Chemically, it is a diterpenoid triepoxide molecule and its chemical formula is C 20 H 24 O 6 . Its five-membered unsaturated lactone ring (D-ring) is crucial for anti-tumor potential and carbonyl group at C-18 position is essential to exert important influence on the interaction between triptolide and the targeted protein(s). It is bio-synthesized from deoxy-D-xylullose-5-phosphate (DOXP) pathway in the cell. Triptolide can induce apoptosis in a number of breast cancer cells by up-regulating different pro-apoptotic and down-regulating different anti-apoptotic molecules. In vitro experiments indicate that it can down regulate several cell cycle related genes and induces S-phase cell cycle arrest. Triptolide treatment can also modulate the expression of different cell signaling molecules, e.g. ERK, NF-κB, FAK, VEGF, β-catenin, AKT etc. In vivo experiments indicate that triptolide can effectively reduce breast tumor growth in the mouse model. Apart from the single drug treatment, triptolide can effectively be applied in combination therapy. Application of Triptolide with other chemotherapeutic drugs, very efficiently check the proliferation of tumor cells which reduces the effective concentration of the commercially available drugs thus reducing their toxic sideeffects. Although triptolide is very effective against a number of diseases, its higher degree of multi-organ toxicity limits its use of further clinical trial. Therefore, to reduce the toxic effects, a number of strategies have been developed which increase its water solubility and at the same time decrease the toxic effect. In this review article, we have addressed how triptolide participates in the antitumor processes in breast can cer cells.

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Molecular Engineered Super‐Nanodevices: Smart and Safe Delivery of Potent Drugs into Tumors

Ding

et al. 2012

Advanced Materials

114

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A super-nanodevice engineered at molecular level integrates various desired properties in a smart and coordinated way, and can "switch on" or "turn off" certain functionalities as required. Importantly, it can break through complex physiological barriers, and then precisely ferry potent toxic triptolide into tumor cells in vivo, thus significantly maximizing the therapeutic efficacy and reducing the drug toxicity.

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Knockout of hepatic P450 reductase aggravates triptolide-induced toxicity

Cited by 67 publications

References 20 publications

Nanostructured lipid carriers as a novel oral delivery system for triptolide: induced changes in pharmacokinetics profile associated with reduced toxicity in male rats

Nanostructured lipid carriers as a novel oral delivery system for triptolide: induced changes in pharmacokinetics profile associated with reduced toxicity in male rats

Triptolide Mediated Amelioration of Breast Cancer via Modulation of Molecular Pathways

Molecular Engineered Super‐Nanodevices: Smart and Safe Delivery of Potent Drugs into Tumors

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