CYP2D6 increases toxicity of the designer drug 4-methylthioamphetamine (4-MTA)

H. Carmo, M. Brulport, M. Hermes, F. Oesch, D. de Boer, F. Remiao, F. Carvalho, M.R. Schon, N. Krebsfaenger, J. Doehmer, L. Bastos Mde, J.G. Hengstler

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

4-Methylthioamphetamine (4-MTA) belongs to a group of new amphetamine derivatives that is usually sold as "ecstasy" or "flatliners" on the illicit drug market. Large interindividual differences in 4-MTA mediated toxicity have been reported in humans. Therefore, we tested whether CYP2D6 or its variant alleles as well as CYP3A4 influence the susceptibility to 4-MTA. For this purpose, we used the colony formation assay with Chinese hamster lung fibroblast V79 cells expressing human wild-type CYP2D6 (CYP2D6*1), the low activity alleles CYP2D6*2, CYP2D6*9, as well as human CYP3A4. The obtained results showed that the expression of wild type CYP2D6*1 clearly enhanced the susceptibility to the cytotoxic effects of 4-MTA compared with the parental cells devoid of CYP-dependent enzymatic activity. Toxicity in V79 CYP2D6*1 was also higher compared to the V79 cell lines expressing the low activity alleles CYP2D6*2 and CYP2D6*9. In contrast to CYP2D6, the CYP3A4 isoenzyme did not enhance 4-MTA toxicity. In conclusion, our results suggest that CYP2D6 rapid metabolizers may be more susceptible to 4-MTA toxicity than CYP2D6 poor metabolizers.
Original languageEnglish
Pages (from-to)236-244
JournalToxicology
Volume229
Issue number3
DOIs
Publication statusPublished - 1 Jan 2007

Cite this

Carmo, H., Brulport, M., Hermes, M., Oesch, F., de Boer, D., Remiao, F., Carvalho, F., Schon, M. R., Krebsfaenger, N., Doehmer, J., Bastos Mde, L., & Hengstler, J. G. (2007). CYP2D6 increases toxicity of the designer drug 4-methylthioamphetamine (4-MTA). Toxicology, 229(3), 236-244. https://doi.org/10.1016/j.tox.2006.10.024