Search

Rhein, the active ingredient of rhubarb, a medicinal and edible plant, is widely used in clinical practice. However, the effects of repeated intake of rhein on liver function and bile acid metabolism are rarely reported. In this work, we investigated the alterations of 14 bile acids and hepatic transporters after rats were administered with rhein for 5 weeks. There was no obvious injury to the liver and kidney, and there were no significant changes in biochemical indicators. However, 1,000 mg/kg rhein increased the liver total bile acid (TBA) levels, especially taurine-conjugated bile acids (t-CBAs), inhibited the expression of farnesoid X receptor (FXR), small heterodimer partner (SHP), and bile salt export pump (BSEP) mRNA, and upregulated the expression of (cholesterol 7α-hydroxylase) CYP7A1 mRNA. Rhein close to the clinical dose (10 mg/kg and 30 mg/kg) reduced the amounts of TBAs, especially unconjugated bile acids (UCBAs), and elevated the expression of FXR and multidrug resistance-associated protein 3 (Mrp3) mRNA. These results denote that rhein is relatively safe to use at a reasonable dose and timing. 30 mg/kg rhein may promote bile acid transport and reduce bile acid accumulation by upregulating the expression of FXR mRNA and Mrp3 mRNA, potentially resulting in the decrease in serum UBCAs. [ABSTRACT FROM AUTHOR]

Tetrahydropalmatine (Tet) exhibit multiple pharmacological activities and is used frequently by clinical practitioners. In this study, we evaluate the in vivo effects of single and repeated oral Tet administrations on CYP1A2, 2D6 and 3A activities in six beagle dogs in a randomized, controlled, open-label, crossover study. A cocktail approach, with dosages of the probe drugs caffeine (3.0 mg/kg), metoprolol (2.33 mg/kg) and midazolam (0.45 mg/kg), was used to measure cytochrome P450 (CYP) metabolic activities. The cocktail was administered orally as a single dose (12 mg/kg) 1 day prior to and 4 days after repeated oral Tet administrations (12 mg/kg three times daily). The probe drugs and their metabolites in plasma were quantified simultaneously by a validated HPLC technique, and non-compartmental parameters were used to evaluate metabolic variables for assessment of CYP inhibition or induction. Tet had no or minor impact on the pharmacokinetics and metabolism of the probe drugs caffeine and metoprolol, CYP1A2 and CYP2D6 substrates, respectively. However, Tet increased AUC0-24 h and decreased AUCratio(0-24 h) (1-hydroxymidazolam/midazolam ratio) for midazolam statistically significant, both in single or multiple dosing of Tet, with up to 39 or 57% increase for AUC0-24 h and 29% or 22 decrease for AUCratio(0-24 h), respectively, in line with previous in vitro findings for its CYP3A4 inhibition. The extensive use of Tet and herbal medicines containing Tet makes Tet a candidate for further evaluation of CYP3A-mediated herb-drug interactions. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Kelisha capsules (KLS) are often used to treat acute diarrhoea, bacillary dysentery, heat stroke, and other diseases. One of its components, Asarum , contains aristolochic acid I which is both nephrotoxic and carcinogenic. However, the aristolochic acid (AA) content in KLS and its toxicity remain unclear. The aims of this study were to quantitatively determine the contents of five aristolochic acid analogues (AAAs) in Asarum and KLS, and systematically evaluate the in vivo toxicity of KLS in rats. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to determine the content of the five AAAs in Asarum and KLS. Sprague–Dawley rats were administered KLS at 0, 0.75, 1.5, and 3.0 g/kg respectively, and then sacrificed after 4 weeks of administration or after an additional 2 weeks of recovery. The endpoints assessed included body weight measurements, serum biochemistry and haematology indices, and clinical and histopathological observations. The AAAs content in Asarum sieboldii Miq. (HB-ESBJ) were much lower than those of the other Asarums. The contents of AA I, AA IVa, and aristolactam I in KLS were in the ranges of 0.03–0.06 μg/g, 1.89–2.16 μg/g, and 0.55–1.60 μg/g, respectively, whereas AA II and AA IIIa were not detected. None of the rats showed symptoms of toxic reactions and KLS was well tolerated throughout the study. Compared to the control group, the activated partial thromboplastin time values of rats in the 1.5 and 3.0 g/kg groups significantly reduced after administration (P < 0.05). In addition, the serum triglycerides of male rats in the 0.75 and 1.5 g/kg groups after administration, and the 0.75, 1.5, 3.0 g/kg groups after recovery were significantly decreased (P < 0.01 or P < 0.001). No significant drug-related toxicological changes were observed in other serum biochemical indices, haematology, or histopathology. The AA I content in KLS met the limit requirements (<0.001%) of the Chinese Pharmacopoeia. Therefore, it is safe to use KLS in the short-term. However, for safety considerations, attention should be paid to the effects of long-term KLS administration on coagulation function and triglyceride metabolism. [Display omitted] • Trace amounts of AA I, AA IVa, and AL I were detected in KLS. • No renal, hepatic, or other tissue damage was observed in long-term administration. • Attention should be paid to the coagulation function and triglyceride metabolism. [ABSTRACT FROM AUTHOR]

Cholestasis is the main manifestation of cholestatic liver disease, which has a risk of progression to end-stage liver disease. Gardeniae Fructus is the dried fruit of Gardeniae jasminoides Ellis, a plant of the Rubiaceae family. Gardeniae Fructus has shown therapeutic potential in cholestasis-related liver diseases and it is generally believed that Gardeniae Fructus ameliorates cholestasis, which could be related to its influence on bile acids (BAs) metabolism. However, the specific targets of Gardeniae Fructus and its impact on enterohepatic circulation of BAs have not yet been fully elucidated. To systematically elucidate the mechanism by which Gardenia extract (GE, total iridoids in Gardeniae Fructus, which contains the predominant and characteristic phytoconstituents of Gardeniae Fructus) ameliorates alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury. Sprague-Dawley rats were orally administered water, obeticholic acid (OCA, 2 mg/kg), or GE (21 and 42 mg/kg) once daily for five days. On the third day, the model was established by administration of a single dose of ANIT (40 mg/kg) by oral gavage. Biochemical and pathological analyses, BA metabolomics, transcriptomics, and qRT-PCR were performed. The profile of BAs in serum and liver confirmed that GE attenuated ANIT-induced acute cholestasis by affecting BA metabolism in a dose-dependent manner. Liver transcriptomic analysis indicated that GE mainly influenced the primary bile acid (PBA) biosynthesis and bile secretion pathways. GE mainly affected PBA biosynthesis in liver by upregulating Cyp8b1 gene expression, thereby significantly reducing the level of total bile acids (TBA). GE mainly promoted PBA excretion from liver into duodenum by upregulating Fxr and Oatp1 gene expression, thereby increasing the excretion of PBA in feces, and inhibiting PBA in liver entering the blood by alternative routes to reduce TBA levels in serum and urine and improve the enterohepatic circulation of BAs. GE attenuated ANIT-induced hepatotoxicity and cholestasis in rats by upregulating Cyp8b1 expression to inhibit BA synthesis in the liver, while also promoting BA excretion via the intestinal-fecal route, and improving enterohepatic circulation of BAs. [Display omitted] • Gardenia extract (GE) attenuated ANIT-induced hepatotoxicity and cholestasis in rats. • GE inhibits the synthesis of BAs in the liver by upregulating the expression of Cyp8b1. • GE promoted BA excretion, and improved enterohepatic circulation of BAs. [ABSTRACT FROM AUTHOR]

The nephrotoxicity and carcinogenicity induced by traditional Chinese medicines (TCMs) containing aristolochic acids (AAs) and related compound preparations have greatly limited their clinical application. While the toxicity of AA-I and AA-II is relatively clear, there are marked differences in the toxic effects of different types of aristolochic acid analogues (AAAs). Thus, the toxicity of TCMs containing AAAs cannot be evaluated based on the toxicity of a single compound. To systematically investigate the toxicity induced by Zhushalian (ZSL), Madouling (MDL) and Tianxianteng (TXT) as representative TCMs derived from Aristolochia. AAA contents in ZSL, MDL and TXT were determined using HPLC. Subsequently, mice were treated for 2 weeks with high (H) and low (L) dosages of TCMs containing total AAA contents of 3 mg/kg and 1.5 mg/kg, respectively. Toxicity was evaluated using biochemical and pathological examination and was based on organ indices. Correlations between AAA contents and induced toxicity were analysed using multiple methods. Of the total AAA content, ZSL contained mainly AA-I and AA-II (>90%, of which AA-I accounted for 49.55%). AA-I accounted for 35.45% in MDL. TXT mainly contained AA-IVa (76.84%) and other AAAs accounted for <10%. Short-term toxicity tests indicated that ZSL and high-dose MDL induced obvious renal interstitial fibrosis and gastric injury, whereas TXT (high and low dosages) caused only slight toxicity. Correlation analysis suggested that AA-I might be the critical hazard factor for toxicity. The toxicity of TCMs containing AAAs cannot be generalised. The toxicity of TXT is relatively low compared with those of ZSL and MDL. The toxicity of Aristolochia depends mainly on the AA-I content; therefore, control of AA-I levels in TCMs and related compound preparations is required to reduce the risk of toxicity associated with the use of Aristolochia herbs in clinical settings. [Display omitted] • Toxicity of herbs containing AAAs cannot be generalised. • Ranking of content of AA-I: ZSL > MDL > TXT. • Ranking of toxicity: ZSL > MDL > TXT. • Aristolochia herb toxicity depends mainly on the AA-I content. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Aristolochia manshuriensis Kom (AMK), belonging to the Aristolochia family, is traditionally used in China to remove heart fire, promote dieresis, restore menstruation, and enhance milk secretion. The active constitutes of AMK are aristolochic acids (AAs, I and II) that are reported to cause serious side effects including nephrotoxicity and carcinogenicity. Aim of the study The tumorigenic role of AMK is far to be understood. We analyzed the toxicity reactions after long-term exposure of AMK in rats. Materials and Methods Sprague–Dawley rats underwent gavage with AMK doses of 51 mg/kg (AMK-1), 253 mg/kg (AMK-2), 508 mg/kg (AMK-3), 1029 mg/kg (AMK-4) or AAs of 15 mg/kg (AAs), and then sacrificed at the 6th, 10th, 14th, 18th, 22th, 26th and 30th weeks. Endpoint measurements included clinical observations, body weights, blood biochemistry, haematology and histomorphological observations. Results Body weight decreased after AMK or AAs treatment in rats. AMK destroyed renal function, and induced anemia in rats. AMK caused kidney, stomach, bladder and subcutaneous tumors in rats. In addition, primary hepatic carcinoma was not observed in rats. Conclusions AMK had significant toxic effects in rats with regard to decreased body weight, diminished renal function, increased anemia and tumor incidence. Kidney, stomach, bladder and subcutaneous tissue are carcinogenic target organs of AMK or AAs, however liver is no- carcinogenic target organ of AMK or AAs in rats. AMK is carcinogenic in rats, and not be safe for humans. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Geniposide, the major active constituent of Fructus Gardeniae (FG), has been widely used to treat various diseases in China. Aim of the study This chronic toxicity study was conducted to investigate the safety of geniposide. Materials and methods Geniposide was administered to Sprague-Dawley (SD) rats of both sexes by oral gavage at dosages of 25, 50, or 100 mg/kg in a volume of 10 mL/kg once daily for 26 weeks. Endpoints included clinical observations, food consumption, body weights, blood biochemistry, haematology, and histomorphological observations. Results The administration of geniposide did not influence animal mortality, the general conditions of the animals, body weights or food consumption. After 4 weeks of administration, significant toxicity was not observed. However, in the 13th week of the toxicity study, a few haematological parameters and some relative organ weights of male rats in the 50 and 100 mg/kg geniposide groups were significantly increased. The percentage of reticulocytes (Retic %) was significantly increased in male and female rats administered 100 mg/kg geniposide. In addition, two female rats in the 100 mg/kg geniposide group showed slight pathological changes in hepatic and renal tissues. Furthermore, in a chronic (26 weeks) toxicity study, differences were detected in alanine aminotransferase (ALT), aspartate aminotransferase (AST), sodium (Na + ), potassium (K + ), white blood cell (WBC), red blood cell (RBC), and haemoglobin (HGB) levels and the relative weights of the liver and spleen in male rats administered 100 mg/kg geniposide. In addition, differences were detected in Retic % and the relative weights of the liver, thymus, and kidneys in female rats administered 100 mg/kg geniposide. Urinalysis results from male and female rats in the 100 mg/kg geniposide group revealed noticeable changes. The histopathological structures of hepatic and renal tissues in the high-dose geniposide group exhibited serious abnormalities and pigment deposition. Conclusion Geniposide affected serum biochemistry, urinalysis, and haematological parameters as well as relative organ weights. The treatment also caused noticeable pathological abnormalities in liver and kidney tissues. Therefore, administration of a high dose of geniposide (100 mg/kg) for 26 weeks could induced obvious liver and kidney damage. [ABSTRACT FROM AUTHOR]

Adverse reactions to traditional Chinese medicine injections involve pseudo-allergic reactions (PARs). However, in clinical practice, "immediate allergic reactions" and PARs in response to these injections are not often differentiated. This study aimed to clarify the type of reactions produced by Shengmai injections (SMI) and elucidate the possible mechanism. A mouse model was used to evaluate vascular permeability. Metabolomic and arachidonic acid metabolite (AAM) analyses were performed using UPLC-MS/MS, and the p38 MAPK/cPLA2 pathway was detected by western blotting. The first exposure to intravenous SMI rapidly and dose-dependently induced edema and exudative reactions in the ears and lungs. These reactions were not IgE-dependent and were likely to be PARs. Metabolomic analysis showed that endogenous substances were perturbed in SMI-treated mice, in which the arachidonic acid (AA) metabolic pathway was the most affected. SMI substantially increased the levels of AAMs in lung, including prostaglandins (PGs), leukotrienes (LTs), and hydroxy-eicosatetraenoic acids (HETEs). The p38 MAPK/cPLA2 signaling pathway was activated after a single SMI dose. Inhibitors of cyclooxygenase-2 and 5-lipoxygenase enzymes reduced exudation and inflammation in the ears and lungs of mice. Production of inflammatory factors that increase vascular permeability may result in SMI-induced PARs, and p38 MAPK/cPLA2 signaling pathway and downstream AA metabolic pathway are involved in the reactions. [Display omitted] • SMI-induced PARs involve a direct inflammatory response without IgE. • AAMs were involved in SMI-induced PARs. • SMI can activate the p38MAPK/cPLA2 signaling pathway. • AA inhibitors Nimesulide and zileuton inhibit AAMs production. [ABSTRACT FROM AUTHOR]

Asarum heterotropoides f. mandshuricum (Maxim.) Kitag. (AH) is widely used to treat influenza, COVID-19, allergic rhinitis, headache, toothache, rheumatoid arthritis, and peptic ulcer. However, its clinical use is controversial due to the concern of aristolochic acid nephropathy (AAN) caused by its component aristolochic acid analogs (AAs). The chronic toxicity of AH decoction and its main components AA IVa (AA-IVa) and aristolactam I (AL-I) was evaluated in mice. AAs contents in AH were quantitated by liquid chromatography-mass spectrometry. A parallel design was employed to examine the potential chronic toxicity of AH decoction at doses equivalent to 0.5, 1.6, and 5.0 g/kg AH (approximately 10–100 times the clinical doses for humans) and its major AA components at doses equivalent to that in 5.0 g/kg AH to mice after consecutive daily oral administration for 12 and 24 weeks, and at 32 weeks after withdrawal for 8 weeks. AH crude herb contained 2.18 μg/g of AA-I, 48.49 μg/g of AA-IVa, and 14.0 μg/g of AL-I. AH decoction contained 5.45 μg/g of AA-IVa and 2.71 μg/g of AL-I. None of AA-II and AA-IIIa were detected in AH. After long-term administration of AH decoction and its major components AA-IVa and AL-I, mice showed no signs of illness or body weight changes. In addition, biochemical and pathohistological examinations showed that long-term administration of AH decoction and its major components AA-IVa and AL-I did not alter 1) serum levels of glutamic-pyruvic transaminase, glutamic oxalacetic transaminase, alkaline phosphatase, creatinine, and urea nitrogen, 2) renal tissue mRNA expression of kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin, and 3) pathological morphology in the mouse liver, kidney, stomach, and bladder. AH has no obvious toxicity to mice and is relatively safe when it is used in the form of decoction. AA-IVa and AL-I, the two major AAs in AH, are not toxic to mice at the dose equivalent to that in the high dose of AH decoction. Considering the limited toxicological data on AH, we recommend that AH decoction medication should not overdose and the duration should not be too long. [Display omitted] • Quantitation of AAs in AH. • Evaluating the toxicity of AH decoction and its AAs. • Providing AH decoction medication suggestion. [ABSTRACT FROM AUTHOR]

Because the toxicity and efficacy of arsenic is closely related to its chemical species, we conducted examinations of arsenic species accumulation and distribution in the rat body after one-time and 30-day realgar administration and then elucidated the probable roles of different arsenic species in the short-term toxicity of realgar. According to ICH M3 guidelines for non-clinical repeated dose toxicity studies and OECD Test guideline TG407 "Repeated Dose 28-Day oral Toxicity Study in Rodents, the doses of realgar set were 10.6 mg/kg, 40.5 mg/kg and 170 mg/kg. Rats were orally administered with realgar for one-tme and 30 days, respectively. Thereafter, biological samples (plasma, urine, liver, kidney, and brain) were obtained from rats and analyzed using high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) to determine realgar metabolism, arsenic species accumulation and distribution. Additionally, the toxicity of realgar in rats was evaluated. The absorption, distribution and elimination half-life of total arsenic species in realgar were 3.33 hs, 16.08 hs and 24.65 hs, respectively. After 30 days of oral administration of realgar in rats, no significant drug-related toxicity occurred in the rats. Dimethylarsenic acid (DMA) is the most abundant arsenic species. The DMA contents of the liver and kidney of the high-dose realgar group were approximately 40-fold and 50-fold higher than those in the corresponding tissues of the control group, respectively. The arsenic species (III) was mainly detected in the liver and its content was about 40-fold higher than that of the control group. MMA was mainly detected in rat kidney, and the MMA content of the realgar treatment group was more than 2000 times higher than that of the control group. Arsenic is rapidly absorbed and distributed over the liver, kidneys and brain, and the distribution and elimination of arsenic in the blood is slow. The realgar doses corresponded to human equivalent doses (HED) of 1.7, 6.4 and 27.2 mg/kg, respectively. Considering that humans are 10 times more sensitive than animals, the realgar dose is equivalent to 0.17, 0.64 and 2.7 mg/kg HED. It can be considered that if patients take no more than 2.7 mg/kg realgar for 2 weeks, there will be no adverse reactions. [ABSTRACT FROM AUTHOR]