Selective Photoaffinity Probe for Monitoring Farnesoid X Receptor Expression in Cultured Cells.

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, is a vital ligand-activated transcriptional factor, which is highly expressed in the liver, intestine, and adrenal gland. However, FXR homeostasis is influenced by many factors, such as diet and circadian rhythm, and the expression of FXR differs in diverse organs. Currently, there is no method to monitor the FXR homeostasis in real time, which restricts us from further investigating the function of FXR under physiological and pathological conditions. In this project, classic FXR agonists were selected to be modified to targeting FXR. The photo-cross-linking diazirine group and alkynyl, a click reaction group, were incorporated to the ligands. Through biorthogonal reaction, fluorophore was linked to the ligands to realize the monitoring of FXR expression in cells.

Gasdermin E-derived caspase-3 inhibitors effectively protect mice from acute hepatic failure.

Programmed cell death (PCD), including apoptosis, apoptotic necrosis, and pyroptosis, is involved in various organ dysfunction syndromes. Recent studies have revealed that a substrate of caspase-3, gasdermin E (GSDME), functions as an effector for pyroptosis; however, few inhibitors have been reported to prevent pyroptosis mediated by GSDME. Here, we developed a class of GSDME-derived inhibitors containing the core structure of DMPD or DMLD. Ac-DMPD-CMK and Ac-DMLD-CMK could directly bind to the catalytic domains of caspase-3 and specifically inhibit caspase-3 activity, exhibiting a lower IC50 than that of Z-DEVD-FMK. Functionally, Ac-DMPD/DMLD-CMK substantially inhibited both GSDME and PARP cleavage by caspase-3, preventing apoptotic and pyroptotic events in hepatocytes and macrophages. Furthermore, in a mouse model of bile duct ligation that mimics intrahepatic cholestasis-related acute hepatic failure, Ac-DMPD/DMLD-CMK significantly alleviated liver injury. Together, this study not only identified two specific inhibitors of caspase-3 for investigating PCD but also, more importantly, shed light on novel lead compounds for treating liver failure and organ dysfunctions caused by PCD.

Ginsenosides synergize with mitomycin C in combating human non-small cell lung cancer by repressing Rad51-mediated DNA repair.

The use of ginseng extract as an adjuvant for cancer treatment has been reported in both animal models and clinical applications, but its molecular mechanisms have not been fully elucidated. Mitomycin C (MMC), an anticancer antibiotic used as a first- or second-line regimen in the treatment for non-small cell lung carcinoma (NSCLC), causes serious adverse reactions when used alone. Here, by using both in vitro and in vivo experiments, we provide evidence for an optimal therapy for NSCLC with total ginsenosides extract (TGS), which significantly enhanced the MMC-induced cytotoxicity against NSCLC A549 and PC-9 cells in vitro when used in combination with relatively low concentrations of MMC. A NSCLC xenograft mouse model was used to confirm the in vivo synergistic effects of the combination of TGS with MMC. Further investigation revealed that TGS could significantly reverse MMC-induced S-phase cell cycle arrest and inhibit Rad51-mediated DNA damage repair, which was evidenced by the inhibitory effects of TGS on the levels of phospho-MEK1/2, phospho-ERK1/2 and Rad51 protein and the translocation of Rad51 from the cytoplasm to the nucleus in response to MMC. In summary, our results demonstrate that TGS could effectively enhance the cytotoxicity of MMC against NSCLC cells in vitro and in vivo, thereby revealing a novel adjuvant anticancer mechanism of TGS. Combined treatment with TGS and MMC can significantly lower the required concentration of MMC and can further reduce the risk of side effects, suggesting a better treatment option for NSCLC patients.

[Update on immune and metabolic dysregulation in major depressive disorder and the implications for drug intervention].

Traditional anti-depressant therapy based on the regulation of monoamine neurotransmitters has shown certain limitations. Recently, accumulating clinical and preclinical studies have reported the tantalizing link between immune dysregulation, inflammatory process and the initiation and exacerbation of major depressive disorder (MDD). With a deepening understanding of neural-immune-metabolic interactions, an immunometabolism driven disease network has attracted huge interests in understanding neuronal inflammation and dysfunction underlying MDD pathogenesis and intervention. This review describes recent data uncovering immunometabolic dysregulation as a key factor in MDD network, with a focus on the recent appreciation of immune-metabolic actions of several anti-depressant compounds. The implications for the discovery of novel antidepressant drugs and clinical management of MDD are discussed.

Effect of root length on epicotyl dormancy release in seeds of Paeonia ludlowii, Tibetan peony.

BACKGROUND AND AIMS: Epicotyl dormancy break in seeds that have deep simple epicotyl morphophysiological dormancy (MPD) requires radicle emergence and even a certain root length in some species. However, the mechanisms by which root length affects epicotyl dormancy break are not clear at present. This study aims to explore the relationship between root length and epicotyl dormancy release in radicle-emerged seeds of Tibetan peony, Paeonia ludlowii, with discussion of the possible mechanisms. METHODS: Radicle-emerged seeds (radicle length 1.5, 3.0, 4.5 and 6.0 cm) were incubated at 5, 10 and 15 °C. During the stratification, some seeds were transferred to 15 °C and monitored for epicotyl-plumule growth. Hormone content was determined by ELISA, and the role of hormones in epicotyl dormancy release was tested by exogenous hormone and embryo culture. KEY RESULTS: Cold stratification did not break the epicotyl dormancy until the root length was ≥6 cm. The indole-3-actic acid (IAA) and GA3 contents of seeds having 6 cm roots were significantly higher than those of seeds with other root lengths, but the abscisic acid (ABA) content was lowest among radicle-emerged seeds. GA3 (400 mg L(-1)) could break epicotyl dormancy of all radicle-emerged seeds, while IAA (200 mg L(-1)) had little or no effect. When grown on MS medium, radicles of naked embryos grew and cotyledons turned green, but epicotyls did not elongate. Naked embryos developed into seedlings on a mixed medium of MS + 100 mg L(-1) GA3. CONCLUSIONS: A root length of ≥6.0 cm is necessary for epicotyl dormancy release by cold stratification. The underlying reason for root length affecting epicotyl dormancy release is a difference in the GA3/ABA ratio in the epicotyl within radicle-emerged seeds, which is mainly as a result of a difference in ABA accumulation before cold stratification.

Bioactive equivalence of combinatorial components identified in screening of an herbal medicine.

PURPOSE: To identify bioactive equivalent combinatorial components (BECCs) in herbal medicines. The exact composition of effective components in herbal medicines is often elusive due to the lack of adequate screening methodology. Herein, we propose a hypothesis that BECCs accounting for the whole efficacy of original herbal medicines could be discovered from a complex mixture of constituents. METHODS: We developed a bioactive equivalence oriented feedback screening method and applied it to discover the BECCs from an herbal preparation Cardiotonic Pill (CP). The operations include chemical profiling of CP, followed by an iterative loop of determining, collecting and evaluating candidate BECCs. RESULTS: A combination of 18 compounds was identified as BECCs from CP, which accounts for 15.0% (w/w) of original CP. We have demonstrated that the BECCs were as effective as CP in cell models and in a rat model of myocardial infarction. CONCLUSIONS: This work answers the key question of which are real bioactive components for CP that have been used in clinic for many years, and provides a promising approach for discovering BECCs from herbal medicines. More importantly, the BECCs could be extended to improve quality control of herbal products and inspire an herbal medicines based discovery of combinatorial therapeutics.

Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats.

AIM: To investigate the potential interactive effects of a high-fat diet (HFD) and valproic acid (VPA) on hepatic steatosis and hepatotoxicity in rats. METHODS: Male SD rats were orally administered VPA (100 or 500 mg·kg⁻¹·d⁻¹) combined with HFD or a standard diet for 8 weeks. Blood and liver samples were analyzed to determine lipid levels and hepatic function biomarkers using commercial kit assays. Low-molecular-weight compounds in serum, urine and bile samples were analyzed using a metabonomic approach based on GC/TOF-MS. RESULTS: HFD alone induced extensive hepatocyte steatosis and edema in rats, while VPA alone did not cause significant liver lesions. VPA significantly aggravated HFD-induced accumulation of liver lipids, and caused additional spotty or piecemeal necrosis, accompanied by moderate infiltration of inflammatory cells in the liver. Metabonomic analysis of serum, urine and bile samples revealed that HFD significantly increased the levels of amino acids, free fatty acids (FFAs) and 3-hydroxy-butanoic acid, whereas VPA markedly decreased the levels of amino acids, FFAs and the intermediate products of the tricarboxylic acid cycle (TCA) compared with the control group. HFD aggravated VPA-induced inhibition on lipid and amino acid metabolism. CONCLUSION: HFD magnifies VPA-induced impairment of mitochondrial ß-oxidation of FFAs and TCA, thereby increases hepatic steatosis and hepatotoxicity. The results suggest the patients receiving VPA treatment should be advised to avoid eating HFD.

[Progress in the role of farnesoid X receptor in metabolic regulation and tumor cell proliferation].

Farnesoid X receptor (FXR) is a ligand-activated transcriptional factor belonged to the superfamily of nuclear receptors. In the past decades, FXR has been found with important roles in the regulation of metabolic homeostasis of bile acids, cholesterol, lipids and carbohydrates. Recent studies further demonstrate the potential protective effect of FXR against metabolic diseases, such as hyperglycemia and hyperlipidemia, as well as inflammatory bowel diseases (IBD). In addition, FXR plays an essential role in liver regeneration, tumor cell proliferation and apoptosis. However, the role of FXR in the development of tumor is still obscure and even with discrepancy. This article reviews the function of FXR in metabolic regulation and recent progress in basic, clinical and pharmacological researches related to tumor cell proliferation involving FXR.

[Evaluation of myocardial ischemia rat model based on metabonomic method of small molecule metabolites of plasma and cardiac muscle].

Isoproterenol (ISO)-induced myocardial ischemia animal model has been widely applied to the study of myocardial ischemia and evaluation of drug efficacy. Metabolic profiling of endogenous compounds can make a deep insight into biochemical process of the ISO-induced myocardial ischemia rats. Herein, rats were treated with ISO (2 mg x kg(-1)) for 10 days. After the model was established by measuring myocardial histopathology and plasma creatine kinase, GC/TOF-MS was used to determine endogenous metabolites in plasma and cardiac muscle of rats, and pattern recognition was used to process the data. Results showed that the plasma metabolic profiling of ISO-induced myocardial ischemia rats was significantly different from that of the control, and it had the tendency to the normal state after the discontinue of ISO injection. Besides, the cardiac muscle of rats treated with ISO for 10 days and the normal cardiac muscle could also be separated clearly. The potential biomarkers in plasma and cardiac muscle of model rats had homogeneity and their own specialty. Biochemical metabolic pathway analysis indicated that this myocardial ischemia model was involved in the alternation of energy metabolism, saccharometabolism, lipid metabolism, nucleoside metabolism and amino acid metabolism, and in relationship with oxidative stress. These findings revealed that metabonomics may be a promising tool to evaluate myocardial ischemia rat model induced by ISO and could further extend the study of pharmacodynamic action of drugs at the molecular level.

Influence of UDP-glucuronosyltransferase polymorphisms on valproic acid pharmacokinetics in Chinese epilepsy patients.

PURPOSE: The aim of this study was to investigate the genetic polymorphisms of UGT1A3, UGT1A6, and UGT2B7 in Chinese epilepsy patients and their potential influence on the pharmacokinetics of valproic acid (VPA). METHODS: The genetic architectures of UGT1A3, UGT1A6, and UGT2B7 in 242 epilepsy patients were detected by DNA sequencing and PCR-restriction fragment length polymorphism. Steady-state plasma concentrations of VPA in 225 patients who had received VPA (approx. 250-1,000 mg/day) for at least 2 weeks were determined and associated with UGT polymorphisms. RESULTS: The allelic distribution of UGT1A3 in our Chinese epilepsy patients was significantly different from that in healthy subjects based on reference data. The standardized trough plasma concentration (C(S)) of VPA was much lower in our patients with the UGT1A3*5 variant than in the wild type carriers (3.24 ± 1.05 vs. 4.68 ± 1.24 µg·kg·mL(-1)·mg(-1), P < 0.01). UGT polymorphisms had no influence on the pharmacokinetic interactions between carbamazepine and VPA. CONCLUSION: Our results suggest that UGT1A3*5 may be an important determinant of individual variability in the pharmacokinetics of VPA and that it may be necessary to increase VPA dose for UGT1A3*5 carriers to ensure its therapeutic range of 50-100 µg/mL.

[Metabonomic phenotype of "formula corresponding to pattern types" based on "qi and yin deficiency pattern" of myocardial ischemia rat model].

In order to explore the scientific connotation of "Fangzhengduiying (formula corresponding to pattern types)", "Qiyinliangxuzheng (Qi and Yin deficiency pattern)" of myocardial ischemia rat model and GC-TOF/MS based metabonomic method were used for comparing the effects of Sheng-mai injection, Salvia injection and propranolol in the present study. After data processing and pattern recognition, Sheng-mai injection showed better efficacy than the other two drugs in accordance with not only visual observation from PLS-DA scores plots but also the number of abnormal endogenous compounds restored to the normal level. Further studies showed that Sheng-mai injection could normalize the level of plasma endothelin-1, the index related to cardiovascular diseases and sleep disorders, which verified the results of metabonomics. Finally, the regulated metabolites and related metabolic pathways were analyzed, and it was supposed that the effects of Sheng-mai injection involved in the alternation of energy metabolism, lipid metabolism, amino acids metabolism, and so on. These findings provided scientific evidence to Shengmai "Fang" used for "Qi and Yin deficiency pattern" correspondingly, indicating that metabonomics has great potential in traditional Chinese medical research, which provides a novel approach and way to modernization of traditional Chinese medicine.

Drug Discovery Inspired from Nuclear Receptor Sensing of Microbial Signals.

Host-microbiota interactions are vital for diverse pathophysiological events and may be targeted for innovative therapeutics. Nuclear receptors (NRs) are versatile host sensors of microbial signals that coordinate diverse environmental cues with local and remote adaptions. Harnessing NR-mediated sensory machinery could provide an alternative lynchpin for gut microbiota-oriented drug discovery strategy.

Silybin alleviates hepatic lipid accumulation in methionine-choline deficient diet-induced nonalcoholic fatty liver disease in mice via peroxisome proliferator-activated receptor α.

Nonalcoholic fatty liver disease (NAFLD) is regarded as the most common liver disease with no approved therapeutic drug currently. Silymarin, an extract from the seeds of Silybum marianum, has been used for centuries for the treatment of various liver diseases. Although the hepatoprotective effect of silybin against NAFLD is widely accepted, the underlying mechanism and therapeutic target remain unclear. In this study, NAFLD mice caused by methionine-choline deficient (MCD) diet were orally administrated with silybin to explore the possible mechanism and target. To clarify the contribution of peroxisome proliferator-activated receptor α (PPARα), PPARα antagonist GW6471 was co-administrated with silybin to NAFLD mice. Since silybin was proven as a PPARα partial agonist, the combined effect of silybin with PPARα agonist, fenofibrate, was then evaluated in NAFLD mice. Serum and liver samples were collected to analyze the pharmacological efficacy and expression of PPARα and its targets. As expected, silybin significantly protected mice from MCD-induced NAFLD. Furthermore, silybin reduced lipid accumulation via activating PPARα, inducing the expression of liver cytosolic fatty acid-binding protein, carnitine palmitoyltransferase (Cpt)-1a, Cpt-2, medium chain acyl-CoA dehydrogenase and stearoyl-CoA desaturase-1, and suppressing fatty acid synthase and acetyl-CoA carboxylase α. GW6471 abolished the effect of silybin on PPARα signal and hepatoprotective effect against NAFLD. Moreover, as a partial agonist for PPARα, silybin impaired the powerful lipid-lowering effect of fenofibrate when used together. Taken together, silybin protected mice against NAFLD via activating PPARα to diminish lipid accumulation and it is not suggested to simultaneously take silybin and classical PPARα agonists for NAFLD therapy.

Extensive intestinal first-pass elimination and predominant hepatic distribution of berberine explain its low plasma levels in rats.

Berberine, one of the most commonly used natural products, exhibits a poor plasma concentration-effect relationship whose underlying mechanisms remain largely unclear. This study was designed to test the hypothesis that extensive first-pass elimination and abundant tissue distribution of berberine may be its specific pharmacokinetic properties. For that, four different dosing routes, intragastric, intraduodenal, intraportal, and intravenous, were used to investigate the gastric, intestinal, and hepatic first-pass elimination of berberine. After intragastric dosing, approximately half of berberine ran intact through the gastrointestinal tract and another half was disposed of by the small intestine, leading to an extremely low extent of absolute oral bioavailability in rats (0.36%). Moreover, the major berberine metabolites were identified and quantified in rat enterocyte S9 fractions, portal vein plasma, and intestinal perfusates; plasma concentrations and tissue distribution of berberine and its major metabolites were determined as well. Data indicated that M1, M2 glucuronide, and M3 were the major metabolites generated from the small intestine and that there was a 70-fold increase in the ratio of the area under the concentration-time curve value for berberine (liver versus plasma). We conclude that intestinal first-pass elimination of berberine is the major barrier of its oral bioavailability and that its high extraction and distribution in the liver could be other important factors that lead to its low plasma levels in rats.

Differential regulations of blood pressure and perturbed metabolism by total ginsenosides and conventional antihypertensive agents in spontaneously hypertensive rats.

AIM: To investigate the regulatory effects of total ginsenosides and the conventional antihypertensive agents (captopril, amlodipine, terazosin and hydrochlorothiazide) on the blood pressure and perturbed metabolism in spontaneously hypertensive rats (SHRs) and to analyze the cause-effect relationships between high blood pressure and the metabolic disorders of hypertension. METHODS: SHRs were administrated with total ginsenosides or the antihypertensive agents for eight weeks. Systolic blood pressure (SP) was measured every week and low-molecular-weight compounds in blood plasma were quantitatively analyzed using a nontargeted high-throughput metabolomic tool: gas chromatography/time of flight mass spectrometry (GC/TOFMS) . The metabolic patterns were evaluated using principal components analysis and potential markers of hypertension were identified. RESULTS: Total ginsenosides and the antihypertensive agents differentially regulated SP and the metabolic pattern in SHRs. Total ginsenosides caused a progressive and prolonged reduction of SP and markedly normalized the perturbed metabolism with 14 of 27 (51.8%) markers of hypertension which were regulated toward normal. Total ginsenosides also reduced free fatty acids' level toward normal levels. In contrast, captopril, amlodipine and terazosin efficiently depressed SP, but had little effect on metabolic perturbation with only 8 (29.6%), 4 (14.8%), and 4 (14.8%) markers, respectively, which were regulated. CONCLUSION: The metabolic changes persisted when the blood pressure was lowered by the conventional antihypertensive agents, suggesting that hypertension may not be the cause of the metabolic perturbation in SHRs.

Herb-drug interactions: in vivo and in vitro effect of Shenmai injection, a herbal preparation, on the metabolic activities of hepatic cytochrome P450 3A1/2, 2C6, 1A2, and 2E1 in rats.

Shenmai injection (SMI), a mixture of Radix Ginseng and Radix Ophiopogonis, is one of the most popular herbal medicinal products and is widely used for the treatment of coronary atherosclerotic cardiopathy and viral myocarditis. The purpose of this study was to investigate the effect of SMI, in vivo and in vitro, on the metabolic activities of hepatic cytochrome CYP450 3A1/2, 2C6, 2E1, and 1A2 in rats. After a single or multiple pretreatment with SMI, the rats were administrated intravenously a cocktail containing midazolam (1 mg/kg), diclofenac (0.5 mg/kg), theophylline (1 mg/kg), and chlorzoxazone (0.5 mg/kg) as probe substrates of rat CYP450 3A1/2, 2C6, 1A2, and 2E1, respectively. Single and multiple SMI pretreatment to rats resulted in a rise of 33.8 % (p < 0.01) and 25.6 % (p < 0.01) in AUC for midazolam, and an increase in AUC for diclofenac by 14.7 % (p < 0.05) and 31.2 % (p < 0.01), respectively. However, the pharmacokinetics of chlorzoxazone and theophylline in rats was not altered markedly. In rat liver microsomes, linear mixed-type inhibition of SMI against the enzyme activities of CYP3A1/2, CYP2C6, and CYP1A2 was shown with IC(50) values of 3.3 %, 2.0 %, and 3.1 % and K(i) values of 3.8 %, 1.5 %. and 1.9 %, respectively. These in vivo and in vitro results demonstrated that SMI had the potential to inhibit the activities of hepatic CYP3A1/2 and CYP2C6, but might not significantly affect CYP1A2 and CYP2E1-mediated metabolism in rats.

Monocyte-derived multipotent cell delivered programmed therapeutics to reverse idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a highly heterogeneous and fatal disease. However, IPF treatment has been limited by the low drug delivery efficiency to lungs and dysfunctional "injured" type II alveolar epithelial cell (AEC II). Here, we present surface-engineered nanoparticles (PER NPs) loading astaxanthin (AST) and trametinib (TRA) adhered to monocyte-derived multipotent cell (MOMC) forming programmed therapeutics (MOMC/PER). Specifically, the cell surface is designed to backpack plenty of PER NPs that reach directly to the lungs due to the homing characteristic of the MOMC and released PER NPs retarget injured AEC II after responding to the matrix metalloproteinase-2 (MMP-2) in IPF tissues. Then, released AST can enhance synergetic effect of TRA for inhibiting myofibroblast activation, and MOMC can also repair injured AEC II to promote damaged lung regeneration. Our findings provide proof of concept for developing a strategy for cell-mediated lung-targeted delivery platform carrying dual combined therapies to reverse IPF.

Simultaneous quantitation of dicaffeoylquinic acids in rat plasma after an intravenous administration of mailuoning injection using liquid chromatography-mass spectrometry.

A high-performance liquid chromatography electrospray ionization mass spectrometry method is developed and validated for the simultaneous quantitation of three major phenolic acids including 1,5-dicaffeoylquinic acid (1,5-DCQA), 3,4-dicaffeoylquinic acid (3,4-DCQA), and 3,5-dicaffeoylquinic acid (3,5-DCQA) in rat plasma. All analytes and internal standard (bergeninum) are extracted from plasma samples by liquid-liquid extraction with isopropanol. The chromatographic separation is accomplished on a stainless-steel column with a gradient 0.1% formic acid-acetonitrile solution as mobile phase at a flow rate of 0.2 mL/min with an operating temperature of 40 degrees C. The selected ion monitoring is performed at m/z 515.2 for 1,5-DCQA, 3,4-DCQA, and 3,5-DCQA, and m/z 327 for the internal standard bergeninum. Linear detection responses are obtained at a concentration range from 0.020 to 5.0 microg/mL for 1,5-DCQA, and 0.039 to 10.0 microg/mL for 3,4-DCQA and 3,5-DCQA. The lower limits of quantitation for 1,5-DCQA, 3,4-DCQA, and 3,5-DCQA are 20, 39, and 39 ng/mL, respectively. The intra- and inter-day precisions (RSD%) are within 11.0%, and the deviations of the assay accuracies are within +/- 12.0% for all analytes. The recoveries are greater than 84.0%. All analytes are proved to be stable during the sample preparation and analytic procedures. The method is successfully applied to the pharmacokinetic study of 1,5-DCQA, 3,4-DCQA, and 3,5-DCQA following an intravenous dose of 10 mL/kg mailuoning injection to rats.

[Thoughts and experimental exploration on pharmacokinetic study of herbal medicines with multiple-components and targets].

The pharmacokinetic research of traditional Chinese medicines (TMC) is an inalienable part of the chain of TCM modernization and plays an important role in the TCM novel drug development. However, the researching method and system that is consistent with the specific characteristics of TCM, i.e., multiple-components and targets, is still lacking. Furthermore, the current understanding of the critical scientific questions of TCM pharmacokinetics remains still unclear. This review makes a brief summary of our recent developments on the pharmacokinetic exploration of TCMs, mainly including integral pharmacokinetic study of multiple components, herbalome analysis both in vitro and in vivo, mechanism based compatibility study for herbal components interactions, and the representative pharmacokinetic study for single herbal compound. Furthermore, the critical scientific questions of TCM pharmacokinetics are discussed based on understanding the requirements of novel drug developments from TCM.

[Advances in study of metabolic activation of carboxyl-acid containing drugs by UGTs].

The metabolic transformation of the drugs containing carboxylic acid groups can lead to the formation of acyl glucuronide metabolites through catalysis by glucuronosyltransferase, and produce pro-acyl glucuronide intermediate metabolites with electronic activity. Then, protein or DNA adducts appeared after a series of non-enzyme or enzyme reactions. These adducts would change the protein activity and potentially lead to idiosyncratic and genotoxicity. In this paper, we discussed the chemical activity, drug-induced mechanisms, distribution and toxicity resulting from this metabolic activation for these drugs, and stated the status and prospects of research in this field.