Nicholas Ekow Thomford1, Kevin Dzobo2, Faustina Adu3, Shadreck Chirikure4, Ambroise Wonkam5, Collet Dandara6. 1. Pharmacogenomics and Drug metabolism Research Group, Division of Human Genetics, Department of Pathology & Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa; School of Medical Sciences, University of Cape Coast, Cape Coast, PMB, Ghana. Electronic address: Nicholas.thomford@uct.ac.za. 2. ICGEB, Cape Town component, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa; Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa. Electronic address: kd.dzobo@uct.ac.za. 3. School of Medical Sciences, University of Cape Coast, Cape Coast, PMB, Ghana. Electronic address: a.faustina@uccsms.edu.gh. 4. Department of Archaeology, University of Cape Town, Cape Town, Rondebosch 7701, South Africa. Electronic address: shadrack.chirikure@uct.ac.za. 5. Pharmacogenomics and Drug metabolism Research Group, Division of Human Genetics, Department of Pathology & Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa. Electronic address: Ambroise.wonkam@uct.ac.za. 6. Pharmacogenomics and Drug metabolism Research Group, Division of Human Genetics, Department of Pathology & Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa. Electronic address: collet.dandara@uct.ac.za.
Abstract
ETHNO-PHARMACOLOGICAL RELEVANCE: Hyptis suaveolens (L) Poit and Boerhavia diffusa Linn are medicinal herbal plants commonly found in the tropics and sub-tropics. They are used to treat various conditions among them boils, dyslipidaemia, eczema, malaria, jaundice and gonorrhoea. Thus, the herbal medicinal extracts are now found as part of some commercial herbal formulations. There has not been adequate characterization of these medicinal herbs on their effects on drug metabolising enzymes. AIM OF THE STUDY: To investigate the effects of extracts of Hyptis suaveolens (HS) and Boerhavia diffusa (BD) on activity of drug metabolising enzymes, CYP1A2, CYP2D6 and CYP3A4, as well predict their potential for herb-drug interaction. A secondary aim was to identify constituent compounds such as polyphenolics, in the crude extract preparations of Hyptis suaveolens and Boerhavia diffusa and measure them for activity. MATERIALS AND METHODS: CYP450 inhibition assays using recombinant CYP450 (rCYP) and fluorescence screening employing individual isozymes (CYP1A2, CYP2D6 and CYP3A4) were used to determine reversible- and time-dependent inhibition (TDI) profiles of extracts of Hyptis suaveolens and Boerhavia diffusa. Inhibition kinetic parameters, Ki and Kinact were also estimated. UPLC-MS employing a Synapt G2 (ESI negative) coupled to a PDA detector was used to identify polyphenolic compounds in crude extracts of Hyptis suaveolens and Boerhavia diffusa. RESULTS: The inhibitory potency of Hyptis suaveolens and Boerhavia diffusa extracts varied among the different enzymes, with CYP1A2 (3.68 ± 0.10µg/mL) being the least inhibited by HS compared to CYP2D6 (1.39 ± 0.01µg/mL) and CYP3A4 (2.36 ± 0.57µg/mL). BD was most potent on CYP3A4 (7.36 ± 0.94µg/mL) compared to both CYP2D6 (17.79 ± 1.02µg/mL) and CYP1A2 (9.48 ± 0.78µg/mL). Extracts of Hyptis suaveolens and Boerhavia diffusa exhibited TDIs on all CYPs. The most prominent phenolic candidates identified in both medicinal herbs using UPLC-MS analysis included caffeic acid, rutin, quercetin, citric acid, ferulic acid and gluconic acid. These phenolic compounds are thought to potentially give HS and BD their therapeutic effects and inhibitory characteristics affecting CYP450 activities. In vivo predictions showed the potential for HS and BD extracts to cause significant interactions if co-administered with other medications. CONCLUSIONS: The study reveals that crude aqueous extracts of HS and BD potentially inhibit drug metabolising isozymes CYP1A2, CYP2D6 and CYP3A4 in a reversible and time-dependent manner. Thus care should be taken when these extracts are co-administered with drugs that are substrates of CYP1A2, CYP2D6 and CYP3A4.
ETHNO-PHARMACOLOGICAL RELEVANCE: Hyptis suaveolens (L) Poit and Boerhavia diffusa Linn are medicinal herbal plants commonly found in the tropics and sub-tropics. They are used to treat various conditions among them boils, dyslipidaemia, eczema, malaria, jaundice and gonorrhoea. Thus, the herbal medicinal extracts are now found as part of some commercial herbal formulations. There has not been adequate characterization of these medicinal herbs on their effects on drug metabolising enzymes. AIM OF THE STUDY: To investigate the effects of extracts of Hyptis suaveolens (HS) and Boerhavia diffusa (BD) on activity of drug metabolising enzymes, CYP1A2, CYP2D6 and CYP3A4, as well predict their potential for herb-drug interaction. A secondary aim was to identify constituent compounds such as polyphenolics, in the crude extract preparations of Hyptis suaveolens and Boerhavia diffusa and measure them for activity. MATERIALS AND METHODS: CYP450 inhibition assays using recombinant CYP450 (rCYP) and fluorescence screening employing individual isozymes (CYP1A2, CYP2D6 and CYP3A4) were used to determine reversible- and time-dependent inhibition (TDI) profiles of extracts of Hyptis suaveolens and Boerhavia diffusa. Inhibition kinetic parameters, Ki and Kinact were also estimated. UPLC-MS employing a Synapt G2 (ESI negative) coupled to a PDA detector was used to identify polyphenolic compounds in crude extracts of Hyptis suaveolens and Boerhavia diffusa. RESULTS: The inhibitory potency of Hyptis suaveolens and Boerhavia diffusa extracts varied among the different enzymes, with CYP1A2 (3.68 ± 0.10µg/mL) being the least inhibited by HS compared to CYP2D6 (1.39 ± 0.01µg/mL) and CYP3A4 (2.36 ± 0.57µg/mL). BD was most potent on CYP3A4 (7.36 ± 0.94µg/mL) compared to both CYP2D6 (17.79 ± 1.02µg/mL) and CYP1A2 (9.48 ± 0.78µg/mL). Extracts of Hyptis suaveolens and Boerhavia diffusa exhibited TDIs on all CYPs. The most prominent phenolic candidates identified in both medicinal herbs using UPLC-MS analysis included caffeic acid, rutin, quercetin, citric acid, ferulic acid and gluconic acid. These phenolic compounds are thought to potentially give HS and BD their therapeutic effects and inhibitory characteristics affecting CYP450 activities. In vivo predictions showed the potential for HS and BD extracts to cause significant interactions if co-administered with other medications. CONCLUSIONS: The study reveals that crude aqueous extracts of HS and BD potentially inhibit drug metabolising isozymes CYP1A2, CYP2D6 and CYP3A4 in a reversible and time-dependent manner. Thus care should be taken when these extracts are co-administered with drugs that are substrates of CYP1A2, CYP2D6 and CYP3A4.
Authors: José Weverton Almeida-Bezerra; Felicidade Caroline Rodrigues; José Jailson Lima Bezerra; Anderson Angel Vieira Pinheiro; Saulo Almeida de Menezes; Aline Belém Tavares; Adrielle Rodrigues Costa; Priscilla Augusta de Sousa Fernandes; Viviane Bezerra da Silva; José Galberto Martins da Costa; Rafael Pereira da Cruz; Maria Flaviana Bezerra Morais-Braga; Henrique Douglas Melo Coutinho; Edward Teixeira de Albergaria; Marcos Vinicius Meiado; Abolghasem Siyadatpanah; Bonglee Kim; Antônio Fernando Morais de Oliveira Journal: Evid Based Complement Alternat Med Date: 2022-03-10 Impact factor: 2.629