プロトピン

The antiarrhythmic effects of protopine on experimental arrhythmia were studied in various animals. Protopine elevated the dose of aconitine needed to induce VP, VT, and VF in rats and increased the dose of strophanthin (strophanthine K) that induced VP in guinea pigs. It also shortened the duration of central arrhythmia induced by aconitine and the duration of arrhythmia induced by benzene-epinephrine (adrenaline) in rats. It prevented rats and mice from developing arrhythmia induced by intravenous calcium chloride and inhalation of chloroform, respectively. In rabbits, the drug raised VFT. It was concluded that protopine has antiarrhythmic effects and may directly inhibit rapid electrical activity of cardiac cells.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.2X10+4(SRC), determined from a structure estimation method(2), indicates that protopine is expected to be immobile in soil(SRC). The estimated pKa of protopine is 4.95(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of protopine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.8X10-16 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Protopine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.4X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2016).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.2X10+4(SRC), determined from a structure estimation method(2), indicates that protopine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.8X10-16 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 24(SRC), from an estimated log Kow of 3.47(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2016).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), protopine, which has an estimated vapor pressure of 6.4X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2)), is expected to exist solely in the particulate phase. Particulate-phase protopine may be removed from the air by wet and dry deposition(SRC). Protopine contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Protopine is a solid. It is used as medication. HUMAN EXPOSURE AND TOXICITY: Using gene reporter assays performed in transiently transfected HepG2 cells, it was demonstrated that the induction of CYP1A1 expression by protopine was associated with mild or negligible activation of the aryl hydrocarbon receptor. CYP1A mRNA levels induced by protopine in both HepG2 cells and human hepatocytes did not result in elevated CYP1A protein or activity levels. ANIMAL STUDIES: Protopine showed an ability to enhance gamma-aminobutyric acid binding to rat brain synaptic membrane receptors in in vitro radiolabeling studies. Protopine has antiarrhythmic effects and may directly inhibit rapid electrical activity of cardiac cells.

Protopine has been found to inhibit histamine H1 receptors and platelet aggregation, and acts as an analgesic. It is one of the compounds with activity like OPIATE ALKALOIDS, acting at OPIOID RECEPTORS. Properties include induction of ANALGESIA or NARCOSIS. Protopine can selectively bind to but do not activate histamine H1 receptors, thereby blocking the actions of endogenous histamine. Classical antihistaminics antagonize or prevent the action of histamine mainly in immediate hypersensitivity. They act in the bronchi, capillaries, and some other smooth muscles, and are used to prevent or allay motion sickness, seasonal rhinitis, and allergic dermatitis and to induce somnolence. Protopine can also function as platelet aggregation inhibitors which antagonize or impair any mechanism leading to blood platelet aggregation, whether during the phases of activation and shape change or following the dense-granule release reaction and stimulation of the prostaglandin-thromboxane system. Protopine inhibits the contractility of isolated cardiac papillary muscles and the proliferation of vascular smooth muscle cells induced by endothelin. It also shortens action potential duration and prolongs the effective refractory period in guinea pig cardiac papillary muscles. The protective effect on rat heart from ischemia_reperfusion damage and the relaxation of rat thoracic aorta induced by protopine have been related to the inhibition of Ca2+ influx through both voltage- and receptor-operated Ca2+ channels. Protopine has been the focus of a large number of biological studies in which they both exhibited, for instance, anti-parasitic activity and only weak cytotoxicity in comparison with other types of isoquinoline alkaloids. Protopine was found to be cytoprotective against oxidative stress induced cell death in vitro. The alkaloid was shown to have anti-arrhythmic, anti-thrombotic, anti-inflammatory, and hepatoprotective effects in animal models. The biological activity of protopine may be associated with its ability to inhibit calcium, sodium, and potassium channels. (PMID:15588728; PMID:21419197; L2104)

Using a structure estimation method based on molecular connectivity indices(1), the Koc of protopine can be estimated to be 1.2X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that protopine is expected to be immobile in soil. The estimated pKa of protopine is 4.95(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/ALTERNATIVE and IN VITRO TESTS/ In this study, we investigated the anticancer effect of protopine on human hormone-refractory prostate cancer (HRPC) cells. Protopine exhibited an anti-proliferative effect by induction of tubulin polymerization and mitotic arrest, which ultimately led to apoptotic cell death. The data suggest that protopine increased the activity of cyclin-dependent kinase 1 (Cdk1)/cyclin B1 complex and that contributed to cell apoptosis by modulating mitochondria-mediated signaling pathways, such as Bcl-2 phosphorylation and Mcl-1 down-regulation. In conclusion, the data suggest that protopine is a novel microtubule stabilizer with anticancer activity in HRPC cells through apoptotic pathway by modulating Cdk1 activity and Bcl-2 family of proteins.

/ALTERNATIVE and IN VITRO TESTS/ The isoquinoline alkaloids protopine and allocryptopine are present in phytopreparations from medicinal plants, such as Fumaria officinalis. Since nothing is known about effects of the alkaloids on the expression of xenobiotic-metabolizing enzymes, we examined whether protopine or allocryptopine affect the expression of cytochromes P450 (CYPs) 1A1 and 1A2 in primary cultures of human hepatocytes and human hepatoma HepG2 cells. In HepG2 cells, protopine and allocryptopine significantly increased CYP1A1 mRNA levels after 24 hr exposure at concentrations from 25 and 10 uM, respectively, as shown by real-time PCR. Both protopine and allocryptopine also dose-dependently increased CYP1A1 and CYP1A2 mRNA levels in human hepatocytes. However, the effects of the tested alkaloids on both cell models were much lower than the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a prototypical CYP1A inducer. Using gene reporter assays performed in transiently transfected HepG2 cells, we demonstrated that the induction of CYP1A1 expression by either protopine or allocryptopine was associated with mild or negligible activation of the aryl hydrocarbon receptor. In contrast to TCDD, CYP1A mRNA levels induced by protopine or allocryptopine in both HepG2 cells and human hepatocytes did not result in elevated CYP1A protein or activity levels as shown by western blotting and EROD assays, respectively. ...

An estimated BCF of 24 was calculated in fish for protopine(SRC), using an estimated log Kow of 3.47(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for protopine is estimated as 2.9X10-16 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that protopine is expected to be essentially nonvolatile from water and moist soil surfaces(2). Protopine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.4X10-10 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Neurotoxicity/ Protopine ... showed an ability to enhance gamma-aminobutyric acid binding to rat brain synaptic membrane receptors in in vitro radiolabeling studies. ...

/ALTERNATIVE and IN VITRO TESTS/ ... In the present study, we studied the anticancer proliferation and adhesion effects of five alkaloids which were isolated from Corydalis yanhusuo. MTT dose response curves, cell migration assay, cell invasion assay, as well as three types of cell adhesive assay were performed on MDA-MB-231 human breast cancer cells. The mechanism of the compounds on inhibiting heterotypic cell adhesion were further explored by determining the expression of epidermal growth factor receptor (EGFR), Intercellular adhesion molecule 1 (ICAM-1), alphav-integrin, beta1-integrin and beta5-integrin by western blotting assay. In five tested alkaloids, only protopine exhibited anti-adhesive and anti-invasion effects in MDA-MB-231 cells, which contributed to the anti-metastasis effect of Corydalis yanhusuo. The results showed that after treatment with protopine for 90 min, the expression of EGFR, ICAM-1, alphav-integrin, beta1-integrin and beta5-integrin were remarkably reduced. The present results suggest that protopine seems to inhibit the heterotypic cell adhesion between MDA-MB-231 cells, and human umbilical vein endothelial cells by changing the expression of adhesive factors.

/ALTERNATIVE and IN VITRO TESTS/ ... In the course of an ongoing human ether-a-go-go-related gene in vitro study, a total of 32 structurally diverse alkaloids of plant origin as well as two semi-synthetically obtained protoberberine derivatives were screened by means of an automated Xenopus oocyte assay. Protopine, (+)-bulbocapnine, (+)-N-methyllaurotetanine, (+)-boldine, (+)-chelidonine, (+)-corynoline, reserpine, and yohimbine reduced the human ether-a-go-go-related gene current by >/= 50% at 100 uM, and were submitted to concentration-response experiments. Our data show that some widely occurring plant-derived alkaloids carry a potential risk for human ether-a-go-go-related gene toxicity.

Ca2+ channel blocker and antiplatelet agent /Protopine hydrochloride/

MEDICATION

It has been found to inhibit histamine H1 receptors and platelet aggregation, and acts as an opioid analgesic.

From opium ... also from the herb Fumaria officinalis L., Chelidonium majus L., and many other Papaveraceae and Fumariaceae.

Protopine hydrochloride (5,6,14,14a-tetrahydro-14a-hydroxy-7-methyl-8H-bis[1,3]benzodioxolo[5,6-a:4,5-g]quinolizinium chloride, C20H20NO5(+)-Cl(-)) is the salt of the isoquinoline alkaloid protopine. It is formed by the action of dilute hydrochloric acid on the protopine free base. The N-methyl and hydroxyl groups are in a trans configuration in the quinolizine ring and the central quinolizine N-C bond is unusually long [1.579 (2) A]. The crystal is a racemate. /Protopine hydrochloride/