Xanthotoxol

Pol J Pharmacol Pharm. 1992 Jan-Feb;44(1):51-7.

Cytotoxic effect of xanthotoxol (8-hydroxypsoralen) on TCTC cells in vitro.[Pubmed: 1437852 ]

The effect of Xanthotoxol (8-hydroxypsoralen) on proliferation of TCTC cells in vitro has been studied.
METHODS AND RESULTS:
Xanthotoxol at concentrations of 5 to 50 micrograms/ml inhibited the growth of cells. In cultures with Xanthotoxol, decreased amount of cell protein, mitotic index, and decreased ability to form a colony, were observed. Moreover, Xanthotoxol disturbed mitoses elevating the number of mitotic cells in the telophase stage. An increase of giant and multinuclear cells was also found. On the basis of these results it can be concluded, that 8-hydroxypsoralen which in comparison with other psoralens is not sensitive to photostimulation, inhibits the cell proliferation anyway.
CONCLUSIONS:
This fact shows that the mechanism of the psoralens activity is to some extent independent from the photostimulation.

Evid Based Complement Alternat Med . 2016;2016:5416509.

Metabolism and Metabolic Inhibition of Xanthotoxol in Human Liver Microsomes[Pubmed: 27034690]

Abstract Cytochrome p450 (CYP450) enzymes are predominantly involved in Phase I metabolism of xenobiotics. In this study, the CYP450 isoforms involved in Xanthotoxol metabolism were identified using recombinant CYP450s. In addition, the inhibitory effects of Xanthotoxol on eight CYP450 isoforms and its pharmacokinetic parameters were determined using human liver microsomes. CYP1A2, one of CYP450s, played a key role in the metabolism of Xanthotoxol compared to other CYP450s. Xanthotoxol showed stronger inhibition on CYP3A4 and CYP1A2 compared to other isoenzymes with the IC50 of 7.43 μM for CYP3A4 and 27.82 μM for CYP1A2. The values of inhibition kinetic parameters (Ki) were 21.15 μM and 2.22 μM for CYP1A2 and CYP3A4, respectively. The metabolism of Xanthotoxol obeyed the typical monophasic Michaelis-Menten kinetics and V max, K m , and CLint values were calculated as 0.55 nmol·min(-1)·mg(-1), 8.46 μM, and 0.06 mL·min(-1)·mg(-1). In addition, the results of molecular docking showed that Xanthotoxol was bound to CYP1A2 with hydrophobic and π-π bond and CYP3A4 with hydrogen and hydrophobic bond. We predicted the hepatic clearance (CL H ) and the CL H value was 15.91 mL·min(-1)·kg(-1) body weight. These data were significant for the application of Xanthotoxol and Xanthotoxol-containing herbs.

Cell Mol Neurobiol. 2013 Jul;33(5):715-22.

Xanthotoxol exerts neuroprotective effects via suppression of the inflammatory response in a rat model of focal cerebral ischemia.[Pubmed: 23619720]

We previously found that Xanthotoxol, one of the major active ingredients in Cnidium monnieri (L.) Cusson, exerts protective effects in a rat model of focal cerebral ischemia/reperfusion injury by alleviating brain edema, inhibiting the neutrophil infiltration, and decreasing the expression of intercellular adhesion molecule-1 (ICAM-1) and E-selectin.
METHODS AND RESULTS:
The present study was designed to further determine the possible mechanisms of action of neuroprotective properties of Xanthotoxol after cerebral ischemia. Transient focal cerebral ischemia/reperfusion model in male Sprague-Dawley rats was induced by 2-h middle cerebral artery occlusion followed by 24-h reperfusion. Xanthotoxol (5 and 10 mg/kg) or vehicle were administered intraperitoneally at 1 and 12 h after the onset of ischemia. At 24 h after reperfusion, we assessed the effect of Xanthotoxol on the blood-brain barrier (BBB) permeability, the production of pro-inflammatory mediators such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-8, nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and the p65 subunit of the transcription factor, nuclear factor-κB (NF-κB) in the cortex after ischemic insult. The results showed that Xanthotoxol treatment significantly attenuated BBB disruption, reduced the IL-1β, TNF-α, IL-8 and NO level, and attenuated the iNOS activity compared with vehicle-treated animals. Further, Xanthotoxol treatment also significantly prevented the ischemia/reperfusion-induced increase in the protein expression of iNOS, COX-2, and the nuclear NF-κB p65.
CONCLUSIONS:
These results, taken together with those of our previous study, suggest that the neuroprotection may be attributed to the ability of Xanthotoxol to attenuate the expression of pro-inflammatory mediators and thereby inhibit the inflammatory response after cerebral ischemia.

Zhong Yao Cai. 2005 Apr;28(4):319-21.

Calcium antagonistic effect of Xanthotoxol on isolated guinea pig atria.[Pubmed: 16104510]

To study the mechanism of depressant effect of Xanthotoxol (XT) on contractility in the isolated guinea pig atria.
METHODS AND RESULTS:
The contractile force of the isolated left atria was determined by tension recording method. In the experiments on contractility of the left atria XT and Verapamil (Ver) significantly depressed the positive staircase phenomena, which was reversed by Ver but not by XT. However, the post-rest potentiation of myocardial contraction in the left atria was only markedly decreased by XT but not by Ver. Furthermore, XT not only attenuated the positive inotropic action, but also delayed the following toxicity response induced by ouabain in the isolated left atria.
CONCLUSIONS:
XT blocked not only the voltage dependent calcium channel, but also the receptor operated calcium channel in the isolated guinea pig atria.

Indian J Physiol Pharmacol. 1979 Apr-Jun;23(2):142-3.

Xanthotoxol (XT) - a potent 5-HT antagonist.[Pubmed: 489098]

Xanthotoxol (XT) - a potent 5-HT antagonist.

J Ethnopharmacol. 1992 Jun;36(3):239-47.

Evaluation of xanthotoxol for central nervous system activity.[Pubmed: 1434683]

Xanthotoxol (XT), 8-hydroxypsoralen, exhibited dose-graded sedative activity in dogs, cats, rats, mice and hamsters.
METHODS AND RESULTS:
At doses of 5-20 mg/kg intraperitoneally (i.p.) in cats and 3-100 mg/kg orally (p.o.) in dogs, XT blocked predatory mouse/rat killing behavior. In mice, XT (10-300 mg/kg i.p.) exhibited a dose-dependent reduction in locomotor activity but was less potent in this regard than reference diazepam (10-100 mg/kg i.p.). XT in mice (0.1-10.0 mg/kg i.p.) and in hamsters (0.1-10.0 mg/kg p.o.) antagonized amphetamine-induced hypermobility but was less potent than diazepam. XT elevated the electrical threshold in foot-shock-induced fighting behavior in rats. XT (0.1-30.0 mg/kg p.o.) potentiated pentobarbital-induced narcosis in hamsters at otherwise subeffective doses of pentobarbital. Conditioned avoidance responses in rats were not significantly altered with 1-3 mg/kg i.p. and 30-100 mg/kg p.o. doses of XT but 300 mg/kg p.o. blocked both conditioned and unconditioned response. Doses of 100-1000 mg/kg i.p. of XT in mice were used to study 48-h acute toxicity of XT and its LD50 was estimated to be 468 mg/kg. Doses of 10, 40 and 80 mg/kg p.o. were used to study the chronic toxicity of XT in rats for 6 months and no side effects or abnormalities in reproductive activity or endocrine integrity were noted.
CONCLUSIONS:
The F1 generation of rats from 6-month XT-treated parents were free of teratogenic effects.

Eur J Med Chem. 2010 Jun;45(6):2559-66.

Synthesis of methyl-substituted xanthotoxol to clarify prooxidant effect of methyl on radical-induced oxidation of DNA.[Pubmed: 20332056]

METHODS AND RESULTS:
4-methyl-8-hydroxylpsoralen (MXan) and 4,9-dimethyl-8-hydroxylpsoralen (DMXan) were synthesized in order to clarify the effect of methyl on the antioxidant effectiveness of Xanthotoxol (8-hydroxylpsoralen, Xan), which were assessed by bleaching beta-carotene in linoleic acid-Triton emulsion, by interacting with 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS+), 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH), and galvinoxyl radical, and by protecting DNA against the oxidation induced by Cu2+/glutathione (GSH) and 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH). Methyl attaching to Xanthotoxol did not affect its ability to protect linoleic acid against autoxidation and to inhibit Cu2+/GSH-induced oxidation DNA, but decreased its ability to scavenge ABTS+ and DPPH, and to protect DNA against AAPH-induced oxidation.
CONCLUSIONS:
Therefore, methyl attenuated the antioxidant effectiveness of Xanthotoxol in radical-induced oxidation of DNA.