| Shen fu decoction is composed of ginseng and aconite,which is a common Chinese medicine compatibility pair in clinical practice.It is mainly used for acute and chronic heart failure,myocardial infarction and other diseases.Panax ginseng C.A.Mey(referred as P.ginseng)and Aconiti Lateralis Radix are two traditional Chinese medicines that have a long history of successful application in the clinic.P.ginseng has been used for the treatment of various diseases such as liver dysfunction,hypertension and cerebrovascular in China,Japan and Korea.Various ginsenosides such as Rgl,Rbl,Re,Rd,Rg3,Rh1 and Rf have all been found to be important constituents in P.ginseng extracts.Aconiti Lateralis Radix is traditional Chinese medicine famed for its toxicity and contains a range of diverse alkaloids such as aconitine,mesaconitine,hypaconitine and benzoylaconitine among many others.Aconitine,mesaconitine and hypaconnitine,which are classed as DAs,have been shown to be the major toxic components in Aconiti Lateralis Radix,and have been known to exert both potent cardiactoxicity and neurotoxicity in several studies.There are several preparations that combine P.ginseng and Radix aconiti lateralis,such as Shen-fu injection and decoction,which can improve heart failure symptoms and rescue hemorrhagic shock,but the mechanism is still unclear.Most interactions related to pharmacokinetics involve drug-metabolizing cytochrome P450(CYP)enzymes.CYP enzymes,which are the main metabolic enzymes involved in phase I metabolism,participate in the metabolism of most endogenous and exogenous substances.There are several CYP450 enzyme isoforms,including CYP1A2,CYP2B,CYP3A4(CYP3A2 in rats),CYP2C9(CYP2C11 in rats),and CYP2E1.CYP3A4 accounts for 60%of all these subtypes.Nuclear receptor superfamily(NRs)has been identified as playing a pivotal role in signal transduction for many xenobiotics.CYP enzyme activities are regulated by NRs,which can increase the efficacy or reduce the toxicity of exogenous substances.Among them,aryl hydrocarbon receptor(AhR)regulates the expression of CYP1A1,constitutive androstane receptor(CAR)regulates CYP2B6,and pregnane X receptor(PXR)regulates CYP3A4.Previous studies have confirmed the pregnane X receptor(PXR)can be mediated drug metabolic enzymes participate in the process of Chinese traditional medicine toxic ingredients in the body,attenuated synergistic effect,but this poison-effect relationship is worth to explore the internal mechanism,so we proposed to carry out based on the compatibility of traditional Chinese medicine(TCM)interaction study of drug metabolic enzymes as explain toxicity after compatibility-provide theoretical basis for efficacy of change.Supported by the national natural science foundation of China s key project "a study on the integrated analysis of the toxicity and efficacy of shenfu decoction based on drug interactions" First,we investigate whether Panax ginseng(P.ginseng)could affect the metabolism of Diester Alkaloids(DAs)derived from Aconiti Lateralis Radix in vivo.Second,to investigate the effects of P.ginseng C.A.Mey(P.ginseng)on the metabolism of diester alkaloids and explore the potential mechanism.Third,to elucidate the mechanism of the protective effects of co-treatment with Panax ginseng and Radix Aconiti Lateralis on heart injury induced by myocardial infarction(MI).As a result,we suggested that compared to the control group,the AUC(0-t)of three DAs increased in both the middle and high dosing group.The Vz/F of three DAs in these groups as well as the CLz/F of aconitine in all P.ginseng groups and the CLz/F of mesaconitine and hypaconitine in P.ginseng middle and high groups were decreased compared to the control group.The clearances of aconitine,mesaconitine,and hypaconitine in the P.ginseng groups were lower than those of the control group.The areas under the curve of midazolam were 2.37 ±1.05,4.96 ± 0.51.,and 6.23 ± 1.30 mg·L-1·h for the low-,medium-,and high-dose P.ginseng groups,respectively,which were higher than that of the control(2.23 ± 0.64 mg·L-1·h).The clearances of midazolam for the medium-(1.87 ± 0.16 L·h-1·kg-1)and high-dose(1.60 ± 0.34 L·h-1·kg-1)P.gins)P.groups were lower than that of the control group(4.66 ±1.43 L·h-1·kg-1).After exposure to P.ginseng extracts,the gene and protein expression levels of CYP3A4 and PXR were decreased.The hepatic metabolism rates of aconitine,mesaconitine,and hypaconntine in HLMs were decreased to 60.37%,21.67%,and 10.11%,respectively,when incubated with ketoconazole,a specific inhibitor for CYP3A.The kinetic plots indicated that the KM and Vmax values of CYP3A4 were 10.08±3.26 μM and 0.12 ± O.0lnmol-mg protein-1.min-1 for aconitine,131.3± 99.75 μM and 0.73 ± 0.44 nmol·mg protein-1·min-1 for mesaconitine,17.05± 9.70 μM and 0.16 ±0.04 nmol-mg protein-1·min-1 for hypaconitine respectively.The in vitro mean intrinsic clearance rates by CYP3A4 were 0.0119,0.0056,0.0091,mL-nmol CYP-1.min-1 for aconitine,mesaconntine and hypaconitine respectively.Radix Aconiti Lateralis or combined with Panax ginseng markedly ameliorated cardiac dysfunction and abnormal ECG manifested by decreased weight/body weight(HW/BW)ratio,BNP and CTNT.Pro-inflammation cytokines(IL-la)significantly decreased,and anti-inflammatory cytokine(IL-10)was significantly enhanced from Panax ginseng single or co-treatment groups compared to model group.HE results suggested that co-treatment had more significant reduced cardiomyocyte cross section area than Panax ginseng or Radix Aconiti Lateralis single.Furthermore,Panax ginseng and/or co-treatment with Radix Aconiti Lateralis administration down-regulated LC3B,beclin1 and AMPK expressions in cardiac tissues,as well as up-regulated p62 expression.In summary,we this paper reveals that orally administrated P.ginseng potentially inhibits the metabolism of DAs from Aconiti Lateralis Radix in rats.P.ginseng inhibited the metabolism of diester alkaloids in vitro,and decreased the CYP3A4 enzyme activity as well as the gene and protein expression of CYP3A4 and PXR in vivo CYP3A4 had a larger effect on diester alkaloid metabolism than the other human CYP isoforms,CYP1A2,CYP2C9,and CYP2E1.Co-treatment with Panax ginseng and Radix Aconiti Lateralis may exert more beneficial effects on heart injury induced by MI in rats than Radix Aconiti Lateralis treatment group,and the underlying mechanism may be associated with the regulation of myocardial autophagy and anti-inflammation effects.This study also revealed the role and status of PXR-CYP3A in the transformation of the poison-effect relationship of shenfu decoction,providing a new target for the integrated analysis of the poison-effect of traditional Chinese medicine.This work also provides a demonstration for the study on the transformation of the poison-effect relationship of traditional Chinese medicine,and provides a scientific basis for the safe and rational use of drugs. |
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