title: CYP2D6 increases toxicity of the designer drug 4-methylthioamphetamine (4-MTA).
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.
authors.affiliation: REQUIMTE, Toxicology Department, Faculty of Pharmacy, University of Porto, Rua Aníbal Cunha 164, 4099-030 Porto, Portugal. helenacarmo@ff.up.pt
authors.forename: Helena
authors.initials: H
authors.lastname: Carmo
authors.forename: Marc
authors.initials: M
authors.lastname: Brulport
authors.forename: Matthias
authors.initials: M
authors.lastname: Hermes
authors.forename: Franz
authors.initials: F
authors.lastname: Oesch
authors.forename: Douwe
authors.initials: D
authors.lastname: de Boer
authors.forename: Fernando
authors.initials: F
authors.lastname: Remião
authors.forename: Félix
authors.initials: F
authors.lastname: Carvalho
authors.forename: Michael R
authors.initials: MR
authors.lastname: Schön
authors.forename: Niels
authors.initials: N
authors.lastname: Krebsfaenger
authors.forename: Johannes
authors.initials: J
authors.lastname: Doehmer
authors.forename: Maria de Lourdes
authors.initials: Mde L
authors.lastname: Bastos
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
mesh_terms: D000662:Amphetamines / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D015198:Designer Drugs / Q000633:toxicity*; D005838:Genotype
chemical_list: D000662:Amphetamines; D015198:Designer Drugs; C078956:4-methylthioamphetamine; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A