NDLI: The cellular toxicology of mitragynine, the dominant alkaloid of the narcotic-like herb, Mitragyna speciosa Korth

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Toxicology Research Vol - 4 Issue - 4

Toxicology Research Vol - 4 Issue - 3

Toxicology Research Vol - 4 Issue - 2

Toxicology Research Vol - 4 Issue - 1

Toxicology Research Vol -3

Toxicology Research Vol -2

Toxicology Research Vol -1

The cellular toxicology of mitragynine, the dominant alkaloid of the narcotic-like herb, Mitragyna speciosa Korth

Content Provider	Royal Society of Chemistry (RSC)
Author	Gooderham, Nigel J. Holmes, Elaine Saidin, Nor Aini Takayama, Hiromitsu
Copyright Year	2015
Abstract	Mitragyna speciosa Korth (Kratom), a herb of the Rubiaceae family is indigenous to southeast Asia. The plant and its dominant alkaloid mitragynine (MIT) are narcotic/analgesic and illicit consumption is widespread in Asia; the toxicological consequences of consumption are poorly documented. We determined cytotoxicity of MIT on human cell lines and report dose and time-dependent stimulation and inhibition of proliferation. Since MIT has powerful opiate-like activity, we focussed on human neuronal SH-SY5Y cell line and found the colony forming ability of cells treated with MIT showed a dose-dependent trend for reduced survival. Studies using metabolically competent MCL-5 cells and chemical inhibitors indicated that CYP 2E1 and 2A6 were involved in the cytotoxicity. Cytotoxicity was preceded by cell cycle arrest mainly at G1 and S phase. To assess whether arrest was due to DNA damage or mutation, we examined genotoxic potential using the L5178 TK+/− mouse lymphoma assay and found that MIT was not genotoxic at the TK locus, even at doses that were highly cytotoxic. To investigate mechanisms of MIT cytotoxicity, we used flow cytometry and annexin V with 7-amino-actinomycin D staining and show apoptosis and necrotic activity. Apoptosis was further supported as MIT rapidly induced the activity of executioner caspases 3/7. However, cytotoxicity of MIT was partially reduced by inclusion of the opioid receptor antagonist naloxone, a μ and δ opioid receptor antagonist, suggesting that cytotoxicity depends in part on opioid signalling, consistent with the known toxicity of other opiates. Based on consumption of 20 leaves per day of Mitragyna speciosa, we estimated daily human exposure to MIT to be about 17 mg MIT for regular consumers, potentially giving plasma concentrations in of 10−9 to 10−7 M. Importantly, fatalities after kratom consumption have been reported to occur in individuals with blood mitragynine concentrations of between 0.45–1.0 μM, substantially lower than the threshold of toxicity predicted from this in vitro report. Clearly the implications of these findings to humans consuming Mitragyna speciosa leaves will require further study, but individuals taking large quantities of these opiate-like materials may be at risk, especially those who have a high CYP2E1 activity, such as heavy alcohol users.
Starting Page	1173
Ending Page	1183
Page Count	11
File Format	HTM / HTML PDF
ISSN	2045452X
Volume Number	4
Issue Number	5
Journal	Toxicology Research
DOI	10.1039/c5tx00113g
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	SH-SY5Y Flow cytometry Mitragynine Opioid receptor Genotoxicity Cytotoxicity Necrosis Blood plasma Alkaloid Rubiaceae Cell cycle Annexin A5 Mitragyna speciosa Mitragyna Ant colony Opioid Lymphoma Massachusetts Institute of Technology Analgesic Naloxone Mouse Asia S phase DNA Kratom Korth MIT Mutation CYP2E1 Apoptosis
Content Type	Text
Resource Type	Article
Subject	Health, Toxicology and Mutagenesis Toxicology

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Cytotoxicity of extract of Malaysian Mitragyna speciosa Korth and its dominant alkaloid mitragynine

Seasonal and Geographic Variation in Alkaloid Content of Kratom (Mitragyna speciosa (Korth.) Havil.) from Thailand.

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Variations in mitragynine content in the naturally growing Kratom (Mitragyna speciosa) population of Thailand

Effects of the extracts from Mitragyna speciosa Korth. leaves on analgesic and behavioral activities in experimental animals

Assessment of Cardiovascular Functioning Among Regular Kratom (Mitragyna speciosa Korth) Users: A Case Series

The cellular toxicology of mitragynine, the dominant alkaloid of the narcotic-like herb, Mitragyna speciosa Korth

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