The cytochrome P450s (CYPs) comprise a large superfamily of a variety of enzymes that serve as major workhorses for metabolizing steroid hormones, lipids, toxins, and xenobiotics. The CYP superfamily genes encode enzymes that function as monooxygenases and catalyze the modification of about 25–30% commonly used drugs [
22,
23]. The
CYP genes are quite polymorphic and they can lead to increased, decreased, or completely absent drug metabolism activity. Among these genes,
CYP2D6 is particularly important and heavily studied. More than 100
CYP2D6 variants have been reported and catalogued at the Pharmacogene Variation Consortium database [
24]. In addition to large numbers of single nucleotide polymorphisms (SNPs), other types of variations—gene deletions, duplications, copy-number variants, and pseudogenes that are close to the gene—make genotyping very challenging.
Many of these variants cause the enzyme to change activity at different levels. The level of CYP2D6 activity decides how an individual responds to the substrate drugs. A standard dosage of the drug may show inadequate efficacy in some individuals and serious toxicity in others. To name a few, the drug substrates of CYP2D6 include atomoxetine (a non-stimulant for ADHD), clozapine (an antipsychotic for schizophrenia), and venlafaxine (an antidepressant), among psychiatric medications, as in
Table 1 [
4,
25]. For these drugs, standard doses will result in higher-than-optimal active levels when individuals have absent or deficient CYP2D6 activity. Thus, the risk of ADRs increases and it may result in treatment failure.
There are substantial variations in
CYP2D6 allele frequencies among different populations [
26,
27]. The wild-type CYP2D6*1 allele shows normal enzyme activity and the extensive or normal metabolizer phenotype. The CYP2D6*2, -*33, and -*35 alleles also belong to this group. Other alleles contain non-functional variant(s), which produce a non-functioning enzyme (*3, *4, *5, *6, *7, and *8) or a decreased-activity enzyme (*10, *17, *29, and *41) [
28]. Intermediate and poor metabolizers are individuals who carry decreased and null CYP2D6 alleles, respectively. Notably, approximately 30% of Asians and Asian descendants are intermediate metabolizers. In these populations, the *10 allele with decreased activity is very common: about 40%, when compared with about 2% in Caucasians [
29]. Thus, a large proportion of Asians belong to intermediate metabolizers than Caucasians [
30]. The African and African American populations also show a large proportion of CYPD6 alleles having sub-optimal activity. The frequencies of the remaining alleles vary depending on the population [
30,
31,
32]. In Caucasians, only small proportions (less than 10%) are poor metabolizers [
30]. In contrast, approximately 40% are extensive/normal metabolizers who carry two copies of *1 allele [
33,
34,
35]. CYP2D6 poor metabolizers show higher levels of amitriptyline (as an example of drug substrates) in the plasma, when compared with extensive metabolizers, after standard doses of amitriptyline are taken [
36]. When individuals carry a CYP2D6 null variant, their risk of developing ADRs becomes, at least, moderately increased [
37]. Because standard dosages may cause to ADRs in poor metabolizers, it is recommended to avoid many tricyclic antidepressants (TCAs) and, instead, take an alternative option, a drug that is not a substrate of CYP2D6 [
38].
Interestingly, copy-number variants were also found in
CYP2D6 genes [
24]. In other words, individuals who carry more than two copies of functional CYP2D6 alleles—three to 13 copies of
CYP2D6 active allele—have been reported. These carriers are CYP2D6 ultrarapid metabolizers. In the case of 13 functional copies, the rate was up to 17 times higher than for individuals with no active CYP2D6 enzyme [
39]. If the drug substrate has increased rate of metabolism, then its active form will not be available and, thus, the therapeutic response will become poor.