ABSTRACT
BACKGROUND: Calycosin (CAL), a type of O-methylated isoflavone extracted from the herb Astralagusmembranaceus (AM), is a bioactive chemical with antioxidative, antiphlogistic and antineoplastic activities commonly used in traditional alternative Chinese medicine. AM has been shown to confer health benefits as an adjuvant in the treatment of a variety of diseases. AIM: The main objective of this study was to determine whether CAL influences the cytochrome P450 (CYP450) system involved in drug metabolism. METHODS: Midazolam, tolbutamide, omeprazole, metoprolol and phenacetin were selected as probe drugs. Rats were randomly divided into three groups, specifically, 5% Carboxymethyl cellulose (CMC) for 8 days (Control), 5% CMC for 7 days + CAL for 1 day (single CAL) and CAL for 8 days (conc CAL), and metabolism of the five probe drugs evaluated using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: No significant differences were observed for omeprazole and midazolam, compared to the control group. T max and t1/2 values of only one probe drug, phenacetin, in the conc CAL group were significantly different from those of the control group (T max h: 0.50±0.00 vs 0.23±0.15; control vs conc CAL). C max of tolbutamide was decreased about two-fold in the conc CAL treatment group (conc vs control: 219.48 vs 429.56, P<0.001). CONCLUSION: Calycosin inhibits the catalytic activities of CYP1A2, CYP2D6 and CYP2C9. Accordingly, we recommend caution, particularly when combining CAL as a modality therapy with drugs metabolized by CYP1A2, CYP2D6 and CYP2C9, to reduce the potential risks of drug accumulation or ineffective treatment.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors/metabolism , Drugs, Chinese Herbal/metabolism , Isoflavones/metabolism , Animals , Cytochrome P-450 Enzyme Inhibitors/chemistry , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Isoflavones/chemistry , Isoflavones/pharmacology , Medicine, Chinese Traditional , Metoprolol/chemistry , Metoprolol/metabolism , Midazolam/chemistry , Midazolam/metabolism , Omeprazole/chemistry , Omeprazole/metabolism , Phenacetin/chemistry , Phenacetin/metabolism , Rats , Tolbutamide/chemistry , Tolbutamide/metabolismABSTRACT
AIM:To investigate whether Yiqi-Wenyang-Huoxue-Huatan formula ( YWHHF) attenuats brain injury induced by hypoxia-hypercapnia pulmonary hypertension ( HHPH) in the rats by inhibiting excessive endoplasmic re-ticulum stress response .METHODS:Healthy SPF male SD rats ( n=50 ) were randomly divided into 5 groups: control group, hypoxia-hypercapnia group, low-dose YWHHF group, middle-dose YWHHF group and high-dose YWHHF group. The rats in control group lived in normal environment , while the rats in other 4 groups were raised for 4 weeks in oxygen tank with low oxygen concentration and high CO 2 concentration .YWHHF was perfused in the rats of low-, middle-and high-dose groups at 0.15, 0.3 and 0.6 g/kg daily, respectively.The rats in hypoxia-hypercapnia group were given isomet-ric distilled water.The surgery was performed on the rats after 4 weeks, and the brain and lung tissues were quickly collect-ed to detect brain water content and observe the morphological changes after mean pulmonary artery pressure recording and heart perfusion .The caspase-3 activity and the apoptotic index of the brain cells were determined .The expression of c-Jun N-terminal kinase (JNK), caspase-12, C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78) at protein and mRNA levels in brain tissues was detected by Western blot and RT-PCR.RESULTS:Compared with con-trol group, mean pulmonary artery pressure, brain water content, brain apoptotic index, caspase-3 activity, and the protein and mRNA levels of JNK, caspase-12, CHOP and GRP78 in the rest 4 groups were increased , and the brain and lung tis-sues had obvious damage under light microscope .Compared with hypoxia-hypercapnia group , mean pulmonary artery pres-sure, brain water content , brain apoptotic index , caspase-3 activity, and the protein and mRNA expression of JNK , caspase-12, CHOP and GRP78 in low-, middle-and high-dose YWHHF groups were decreased , and the pathological dam-age of the brain and lung tissues was obviously reduced under light microscope .These changes in middle-dose YWHHF group were the most significant .CONCLUSION:YWHHF effectively relieves the brain injury induced by HHPH in rats , which may be associated with inhibiting excessive endoplasmic reticulum stress response .
ABSTRACT
AIM:To investigate whether Yiqi-Wenyang-Huoxue-Huatan formula ( YWHHF) attenuats brain injury induced by hypoxia-hypercapnia pulmonary hypertension ( HHPH) in the rats by inhibiting excessive endoplasmic re-ticulum stress response .METHODS:Healthy SPF male SD rats ( n=50 ) were randomly divided into 5 groups: control group, hypoxia-hypercapnia group, low-dose YWHHF group, middle-dose YWHHF group and high-dose YWHHF group. The rats in control group lived in normal environment , while the rats in other 4 groups were raised for 4 weeks in oxygen tank with low oxygen concentration and high CO 2 concentration .YWHHF was perfused in the rats of low-, middle-and high-dose groups at 0.15, 0.3 and 0.6 g/kg daily, respectively.The rats in hypoxia-hypercapnia group were given isomet-ric distilled water.The surgery was performed on the rats after 4 weeks, and the brain and lung tissues were quickly collect-ed to detect brain water content and observe the morphological changes after mean pulmonary artery pressure recording and heart perfusion .The caspase-3 activity and the apoptotic index of the brain cells were determined .The expression of c-Jun N-terminal kinase (JNK), caspase-12, C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78) at protein and mRNA levels in brain tissues was detected by Western blot and RT-PCR.RESULTS:Compared with con-trol group, mean pulmonary artery pressure, brain water content, brain apoptotic index, caspase-3 activity, and the protein and mRNA levels of JNK, caspase-12, CHOP and GRP78 in the rest 4 groups were increased , and the brain and lung tis-sues had obvious damage under light microscope .Compared with hypoxia-hypercapnia group , mean pulmonary artery pres-sure, brain water content , brain apoptotic index , caspase-3 activity, and the protein and mRNA expression of JNK , caspase-12, CHOP and GRP78 in low-, middle-and high-dose YWHHF groups were decreased , and the pathological dam-age of the brain and lung tissues was obviously reduced under light microscope .These changes in middle-dose YWHHF group were the most significant .CONCLUSION:YWHHF effectively relieves the brain injury induced by HHPH in rats , which may be associated with inhibiting excessive endoplasmic reticulum stress response .