Abstract
The ultrarapid CYP2D6 metabolizer (UM) phenotype is caused by CYP2D6 gene duplications in some, but not all, UM individuals. CYP2D6 and the adjacent pseudogene CYP2D7 are highly homologous; however, CYP2D7 harbors a premature stop codon, which is absent in carriers of the rare CYP2D7 variant rs530303678. We addressed whether rs530303678 could generate a functionally active protein, causing the UM phenotype. However, unlike CYP2D6 variants, two CYP2D7 rs530303678 variant isoforms, previously described in liver, showed neither significant protein expression nor catalytic activity toward the CYP2D6 substrates bufuralol or dextromethorphan. We conclude that loss of the stop codon in CYP2D7 does not result in the generation of enzymatically active protein in human liver and thus, cannot cause the UM phenotype.
References
- 1 . Ten years’ experience with the CYP2D6 activity score: a perspective on future investigations to improve clinical predictions for precision therapeutics. J. Pers. Med. 8(2), pii:E15 (2018).
- 2 . The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene and a pseudogene. Am. J. Hum. Genet. 45(6), 889–904 (1989).
- 3 Frequency of the frame-shifting CYP2D7 138delT polymorphism in a large ethnically diverse sample population. Drug Metab. Dispos. 35(8), 1251–1253 (2007).
- 4 . A frameshift mutation and alternate splicing in human brain generate a functional form of the pseudogene cytochrome P4502D7 that demethylates codeine to morphine. J. Biol. Chem. 279(26), 27383–27389 (2004).
- 5 . CYP2D7 splice variants in human liver and brain: does CYP2D7 encode functional protein? Biochem. Biophys. Res. Commun. 336(4), 1241–1250 (2005).
- 6 . Expression and functional analysis of CYP2D6.24, CYP2D6.26, CYP2D6.27 and CYP2D7 isozymes. Drug Metab. Dispos. 37(1), 1–4 (2009).
- 7 Functional characterization of 34 CYP2A6 allelic variants by assessment of nicotine C-oxidation and coumarin 7-hydroxylation activities. Drug Metab. Dispos. 45(3), 279–285 (2017).
- 8 Functional characterization of 17 CYP2D6 allelic variants (CYP2D6.2, 10, 14A-B, 18, 27, 36, 39, 47–51, 53–55 and 57). Drug Metab. Dispos. 36(12), 2460–2467 (2008).
- 9 . Characterization of cytochrome P450 2D6.1 (CYP2D6.1), CYP2D6.2 and CYP2D6.17 activities toward model CYP2D6 substrates dextromethorphan, bufuralol and debrisoquine. Drug Metab. Dispos. 30(5), 595–601 (2002).
- 10 Functional characterization of wild-type and 49 CYP2D6 allelic variants for N-desmethyltamoxifen 4-hydroxylation activity. Drug Metab. Pharmacokinet. 29(5), 360–366 (2014).