In vitro and in vivo effect of 3-Para-fluorobenzoyl-propionic acid on rat liver mitochondrial permeability transition pore opening and lipid peroxidation

Adeola O. Olowofolahan 1 , Omosola L. Bolarin 1 , and Olufunso O. Olorunsogo 1
  • 1 Laboratory for Membrane Biochemistry Research and Biotechnology, Department of Biochemistry, University of Ibadan, Nigeria

Abstract

The opening of mitochondrial permeability transition (mPT) pore is a well recognized important event in the execution of mitochondrial-mediated apoptosis. Some bioactive compounds induce apoptosis in tumour cells via the induction of mPT pore opening. This study therefore investigated the effect of 3-Para-fluorobenzoyl-propionic acid (3PFBPA), a metabolite of haloperidol on mPT pore, mitochondrial ATPase activity (mATPase), mitochondrial lipid peroxidation (mLPO) and cytochrome c release (CCR). Thirty-two male Wistar rats, were acclimatized for 14 days in clean cages. After 30 days of treatment, they were sacrificed and the liver mitochondria isolated using differential centrifugation. The mPT pore, mATPase, mLPO and CCR were determined by standard methods using a spectrophotometer. The mPT pore opening was induced by 3PFBPA by 1.4, 3.6, 5.6, 6.6 and 7.4 folds, when compared with the control. Also, there was release of cytochrome c and enhancement of mATPase activity by 3PFBPA. The results also show that 3PFBPA reduced lipid peroxidation. However, oral administration of 3PFBPA at 50, 100 and 200 mg/kg did not have any effect on mPT pore opening and mATPase activity when compared with the control but there was inhibition of mLPO. These findings suggested the pharmacological potential of 3PFBPA against the pathological processes related to insufficient apoptosis (based on the in vitro data) and oxidative stress due to its anti-lipidperoxidative effect.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • Appaix, F., Minatchy, M., Riva-Lavieille, C., Olivaires, J., Antonnson, B., Saks, V.A., 2000, Rapid spectrophotometric method for quantitation of cyctochrome c release from isolated mitochondria or permealized cells revisited. Biochimica et Biophysica Acta, 1457: 175-181.

  • Bassir, O., 1963, Improving the level of nutrition. West African Journal of Biology and Applied Chemistry, 7: 32-40.

  • Bernardi, P., Di Lisa, F., 2015, The mitochondrial permeability transition pore: Molecular nature and role as a target in cardioprotection. Journal of Molecular and Cellular Cardiology, 78:100–106.

  • Bowen, W.D., Moses, E.L., Tolentino, P.J., Walker, J.M., 1990, Metabolites of haloperidol display preferential activity at σ receptors compared to dopamine D-2 receptors. Eur J Pharmacol, 177: 111–118.

  • Green, D.R., Kroemer, G., 2004, The pathophysiology of mitochondrial cell death. Science, 305 (5684): 626–629.

  • Huang, S., Hlzel, M., Knijnenburg, T., 2012, MED12 controls the response to multiple cancer drugs through regulation of TGF-beta receptor signaling. Cell, 151: 937-50.

  • HyeonSoo Kim, Minseok Song, SanatombiYumkham, Jang Hyun Choi, Taehoon Lee, Joseph Kwon, Sung Jae Lee, Jong-In Kim, Kang Woo Lee, Pyung-Lim Han, Seung Woo Shin, Ja-Hyun Baik, Yong Sik Kim, Sung Ho Ryu and Pann-GhillSuh, 2006, Identification of a new functional target of haloperidol metabolite: implications for a receptor-independent role of 3-(4-fluorobenzoyl) propionic acid. Journal of neurochemistry, 2006: 10-13.

  • Jiang, Y., Yang, J., Yang, C., 2013, Vitamin K4 induces tumor cytotoxicity in human prostate carcinoma PC-3 cells via the mitochondria-related apoptotic pathway. Pharmazie, 68: 442-448.

  • Kallenberger S., Joël B., Juliane C., Carmen F., Peter, K.S, Stefan L., 2014, Intra- and Interdimeric Caspase-8 Self-Cleavage Controls Strength and Timing of CD95-Induced Apoptosis. Sci. Signal, 7 (316): 23.

  • Lee, E., Min, H., Park, H., Chung, H., Kim, S., Han, Y., Lee, S., 2004, G2/M cell cycle arrest and induction of apoptosis by a stilbenoid, 3,4,5- trimethoxy-49-bromo-cis-stilbene, in human lung cancer cells. Life Sci, 75: 2829–2839.

  • Lowry, O.H., Rosenbrough, N.J., Farr, A.L., Randall, R.J., 1951, Protein measurement with Folin phenol reagent. J Biol Chem, 193 (1): 265-275.

  • Martins, K.R., 2006, Targeting apoptosis with dietary bioactive agents. Minireview, 117-130.

  • McIlwain, D. R., Berger, T., Mak, T.W., 2013, Caspase functions in cell death and disease. Cold Spring Harbor Perspecives in Biology, 1 (5): 4.

  • MdSoriful Islam, Most Mauluda Akhtar, James H. Segars, Mario Castellucci, Pasquapina Ciarmela, 2017, Molecular targets of dietary phytochemicals for possible prevention and therapy of uterine fibroids: Focus on fibrosis, Critical Reviews in Food Science and Nutrition, 57 (17): 3583-3600.

  • Olorunsogo, O.O., Malomo, S.O., 1985, Sensitivity of Oligomycininhibited respiration of isolated rat liver mitochondria to perfluidone, a fluorinated arylalkylsulfonamide. Toxicology, 35(3): 231-40.

  • Olorunsogo, O.O., Bababunmi, E.A., Bassir, O., 1979, Uncoupling effect of N-phosphonomethylglycine on rat liver mitochondria. Biochem. Pharm, 27: 925-927.

  • Olowofolahan, O.A., Ezekiel, C.D., Olorunsogo, O.O., 2019, Induction of Mitochondrial Membrane Permeability Transition Pore Opening and DNA Fragmentation by Certain Solvent Fractions of Mangifera indica. Archives of Basic and Applied Medicine, 7: 123 – 129.

  • Reed, J., 2004, Apoptosis mechanisms: implications for cancer drug discovery. Oncology, 18:11–20.

  • Ruberto, G., Baratta, M.T., Deans, S.G, Dorman, H.J., 2000, Antioxidant and antimicrobial activity of Foeniculum vulgare and Crithmum maritimum essential oils. Planta Med, 66: 687–693.

  • Varshney, R., Kale, R.K., 1990, Effect of calmodulin antagonists on radiation-induced lipid peroxidation in microsomes. Int. Radiat Biol, 58: 773-743.

OPEN ACCESS

Journal + Issues

Search