Alternative titles; symbols
HGNC Approved Gene Symbol: CYP2D6
Cytogenetic location: 22q13.2 Genomic coordinates (GRCh38): 22:42,126,499-42,130,810 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q13.2 | {Codeine sensitivity} | 608902 | Autosomal recessive | 3 |
| {Debrisoquine sensitivity} | 608902 | Autosomal recessive | 3 |
The hepatic cytochrome P450 system is responsible for the first phase in the metabolism and elimination of numerous endogenous and exogenous molecules and ingested chemicals. P450 enzymes convert these substances into electrophilic intermediates which are then conjugated by phase II enzymes (e.g., UDP glucuronosyltransferases, see 191740; N-acetyltransferases, see 108345) to hydrophilic derivatives that can be excreted (Nebert, 1997).
The P450II superfamily comprises at least 11 subfamilies designated by letter according to the system of nomenclature recommended by an international committee (Nelson et al., 1996; Nebert et al., 1987; Nelson et al., 2004). Although humans probably have approximately 60 unique P450 genes within 14 subfamilies (Nelson et al., 1996), only a subset are responsible for metabolism of the vast majority of prescribed and over-the-counter drugs (see, e.g., CYP1A2, 124060; CYP2A6, 122720; CYP2C19, 124020; CYP2D6; CYP2E1, 124040; CYP3A4, 124010; and CYP4A11, 601310).
Gonzalez et al. (1988) used rat anti-db1 (Gonzalez et al., 1987) to isolate the human P450 DB1 gene from a human liver cDNA library. The deduced 497-amino acid protein shares 73% sequence identity with the rat protein.
Kimura et al. (1989) determined that the CYP2D6 gene contains 9 exons.
By somatic cell hybridization, Gonzalez et al. (1988) mapped the P450DB1 gene to chromosome 22. By somatic cell hybridization, in situ hybridization, and linkage analysis, Gough et al. (1993) mapped the CYP2D6 gene to 22q13.1.
Gonzalez et al. (1987) mapped the mouse db1 gene to chromosome 15.
Pseudogenes
Kimura et al. (1989) identified 3 genes that compose the CYP2D gene cluster located distal to IGLC (147220) on chromosome 22 (q11.2-qter). One of these, CYP2D8P, was found to be a pseudogene, while the CYP2D7 gene contained a single reading frame-disrupting insertion in its first exon.
Distlerath and Guengerich (1984) found that antibodies to a cytochrome P450 shown to be responsible for debrisoquine 4-hydroxylation in rats inhibited the oxidation of debrisoquine and sparteine, encainide, and propranolol in human liver microsomes. All 4 of the drugs had been associated with the poor metabolizer (PM) phenotype (608902) in humans. The antibodies did not inhibit the oxidation of 7 other cytochrome P450 substrates.
Guengerich et al. (1986) stated that 9 forms of cytochrome P450 had been purified to electrophoretic homogeneity from human liver microsomes. These included the enzymes involved in debrisoquine 4-hydroxylation, phenacetin O-deethylation (124060), and mephenytoin 4-hydroxylation (124020), 3 reactions characterized by genetic polymorphism in humans. Different forms of P450 are involved in the 3 reactions. Guengerich et al. (1986) presented evidence that the P450 nifedipine oxidase is separate from these others (see 124010). Nifedipine is a calcium-channel blocker which about 17% of the population cannot metabolize rapidly as judged by in vivo studies (Kleinbloesem et al., 1984).
Harmer et al. (1986) found no correlation between the acetylator (see 243400) and the sparteine hydroxylation phenotypes. The findings were consistent with the fact that the N-acetyltransferase enzyme is cytosolic in liver and jejunal mucosa, whereas the polymorphic enzyme that governs hydroxylation of sparteine, debrisoquine, and other drugs is a liver P450.
Occurrence of a lupus-like syndrome in patients treated with procainamide (see 152700) has limited the clinical use of this antiarrhythmic drug. Lessard et al. (1997) demonstrated that CYP2D6 is the major isozyme involved in the formation of N-hydroxyprocainamide, a metabolite potentially involved in the drug-induced lupus syndrome observed with procainamide. By studying the in vivo oxidation of procainamide in man, Lessard et al. (1999) suggested that CYP2D6 is involved in the in vivo aliphatic amine deethylation and N-oxidation of procainamide at its arylamine function.
Thum and Borlak (2000) investigated the gene expression of major human cytochrome P450 genes in various regions of 2 normal hearts and explanted hearts from 6 patients with dilated cardiomyopathy and 1 with transposition of the arterial trunk. CYP2D6 mRNA was predominantly expressed in the right ventricle; a strong correlation between tissue-specific gene expression and enzyme activity was found. Thum and Borlak (2000) noted that the unilateral expression of the CYP2D6 gene in right ventricular tissue was important because of the enzyme's key role in the metabolism of beta-blockers.
Drug Metabolism
Gonzalez et al. (1988) identified 3 variant DB1 mRNAs in liver samples from several poor metabolizers (PMs) of debrisoquine (608902). The variant mRNAs were products of a mutant gene producing incorrectly spliced pre-mRNA, thus providing a molecular explanation for the defect. The authors noted that the frequency of mutant alleles is approximately 35 to 43%. Skoda et al. (1988) identified restriction fragment length polymorphisms associated with the P450DB1 locus that were observed more frequently in individuals with the PM phenotype. A different, 29-kb XbaI fragment was present in all individuals with the wildtype extensive metabolizer (EM) phenotype. The authors proposed that these polymorphisms identified 2 independent mutant alleles of the P450DB1 gene. Eight additional RFLPs associated with this gene were also reported.
In 20 individuals with poor metabolism of debrisoquine, Gough et al. (1990) identified a splice site mutation in the CYP2D6 gene (124030.0001), yielding a protein with no functional activity. This allele has been termed CYP2D6*4.
Mura et al. (1993) noted that wildtype extensive metabolizers exhibit highly variable metabolic activity. In a study of French-Canadian families, they found that a subgroup of EM individuals were heterozygous for a mutant allele, and that a second level of heterogeneity was detected among individuals not carrying mutations but who had a polymorphic BamHI-defined DNA haplotype. Different combinations of haplotypes were associated with differences in CYP2D6 metabolic activity. Mura et al. (1993) suggested that genetic and phenotypic heterogeneity with EMs may underly conflicting data on the relation between CYP2D6 activity and susceptibility to cancer.
Bertilsson et al. (1993) and Johansson et al. (1993) showed that the genetic basis of the ultrarapid metabolizer phenotype (see 608902) is gene duplication or amplification of functionally active CYP2D6 genes, resulting in higher levels of enzyme being expressed. In 5 individuals from 2 families who had metabolic ratios (MRs) of less than 0.1 (ultrarapid phenotype), Johansson et al. (1993) found 12 extra copies of the CYP2D6 gene associated with a variant, termed CYP2D6L (124030.0007). Other individuals with multiduplicated CYP2D6 genes in 3, 4, or 5 copies on 1 allele have been seen (Dahl et al., 1995; Aklillu et al., 1996).
Tyndale et al. (1997) noted that oral opiates (i.e., codeine, oxycodone, and hydrocodone) are metabolized by CYP2D6 to metabolites of increased activity (i.e., morphine, oxymorphone, and hydromorphone). Among a group of 83 individuals who were oral opiate-dependent, Tyndale et al. (1997) found none who were PMs, either phenotypically or genotypically (homozygous for the deficient CYP2D6*3 or CYP2D6*4 alleles); 4% of 276 individuals who were never drug-dependent were PMs. The authors suggested that the PM genotype was a protection factor for oral opiate dependence (odds ratio greater than 7). This conclusion was challenged by Mikus et al. (1998). Tyndale et al. (1998) defended their stand.
Gasche et al. (2004) described life-threatening opioid intoxication in a patient given small doses of codeine for the treatment of a cough associated with bilateral pneumonia. Codeine is bioactivated by CYP2D6 into morphine, which then undergoes further glucuronidation. CYP2D6 genotyping showed that the patient had 3 or more functional alleles (124030.0008), a finding consistent with ultrarapid metabolism of codeine. Gasche et al. (2004) attributed the toxicity to this genotype, in combination with inhibition of CYP3A4 activity by other medications and a transient reduction in renal function.
Liou et al. (2006) investigated the frequencies of the poor and ultrarapid metabolizer-associated alleles of 5 cytochrome P450 genes in 180 Han Chinese volunteers in Taiwan and found that more than 50% of the CYP2C19 (124020) and CYP2D6 genotypes were associated with the intermediate metabolizer phenotype. Liou et al. (2006) suggested that this might explain why drug dosages used in clinical trials with East Asian participants are usually lower than those used in trials with Western participants.
In a group of 115 white patients with Alzheimer disease (AD; 104300) taking donepezil, Pilotto et al. (2009) found that nonresponders had a significantly higher frequency of the -1584G allele (rs1080985) in the CYP2D6 gene compared to responders (58.7% vs 34.8%, p = 0.013), with an odds ratio of 3.43 for poor response. The -1584G allele is associated with higher enzymatic activity and more rapid drug metabolism. The findings suggested that the rs1080985 SNP in the CYP2D6 gene may influence the clinical efficacy of donepezil in AD patients.
Schroth et al. (2009) performed a retrospective analysis of German and U.S. cohorts of women with tamoxifen-treated hormone receptor-positive breast cancer (114480) to determine whether CYP2D6 variation is associated with clinical outcome. The median follow-up of the 1,325 patients was 6.3 years. At 9 years of follow-up, the recurrence rates for breast cancer were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediate metabolizers, and 29.0% for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively. Schroth et al. (2009) concluded that there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes in tamoxifen-treated breast cancer.
Association with Parkinson Disease
In a study of over 500 patients with Parkinson disease (PD; 168600) and matched controls, Payami et al. (2001) found no association between the CYP2D6*4 allele (124030.0001) underlying a poor metabolizer phenotype and the age of onset of PD. Instead, the frequency of the *4 allele appeared to increase with age in the general population, a finding that suggested a selective advantage of the allele over the wildtype. Their results also suggested that the *4 allele may be protective against cancer.
In a study of 247 patients with PD, Elbaz et al. (2004) found an interaction between the CYP2D6*4 allele and exposure to pesticides with regard to development of the disease. Although there was no association between carriers of the CYP2D6*4 allele and development of PD in those with no exposure to pesticides, there was an association among those with the PM allele and exposure to pesticides. Individuals homozygous for the CYP2D6*4 allele who had professional exposure to pesticides had a significantly increased risk of PD compared to those without the allele and without exposure (odds ratio of 4.74); homozygous PM individuals with moderate 'gardening' exposure to pesticides showed a similar trend toward development of PD (odds ratio of 2.75). Deng et al. (2004) examined 3 PM alleles, CYP2D6*4, CYP2D6*3, and CYP2D6*5, in a group of 393 PD patients. At the most extreme, patients who were homozygous for the PM alleles and had weekly exposure to pesticides showed a significant increased risk for the disease (odds ratio of 8.41). Heterozygotes with weekly exposure had an odds ratio of 3.27. The authors suggested an interaction between pesticide exposure and CYP2D6 polymorphism in the development of PD.
Other Disease Associations
Brown et al. (2000) performed a linkage study of chromosome 22 in 200 families with ankylosing spondylitis (AS; 106300)-affected sib pairs. While homozygosity for PM alleles was found to be associated with AS, heterozygosity for the most frequent PM allele (CYP2D6*4) was not associated with increased susceptibility to AS. Significant within-family association of CYP2D6*4 alleles and AS was demonstrated. Weak linkage was also demonstrated between CYP2D6 and AS. The authors hypothesized that altered metabolism of a natural toxin or antigen by the CYP2D6 gene may increase susceptibility to AS.
Sachse et al. (1997) determined CYP2D6 allele frequencies in 589 unrelated German volunteers and correlated enzyme activity measure by phenotyping with dextromethorphan or debrisoquine. The frequency of the CYP2D6*1 wildtype allele coding for the extensive metabolizer phenotype was 0.364. The alleles coding for slightly (CYP2D6*2) or moderately (*9 and *10) reduced activity (intermediate metabolizer phenotype, IM) showed frequencies of 0.324, 0.018, and 0.015, respectively. Frequencies of alleles with complete deficiency (poor metabolizer phenotype) were 0.207 (CYP2D6*4; 124030.0001), 0.020 (CYP2D6*3; 124030.0006 and CYP2D6*5; 124030.0002), 0.009 (CYP2D6*6; 124030.0003), and 0.001 (*7, *15, and *16). The defective CYP2D6 alleles *8, *11, *12, *13, and *14 were not found. CYP2D6 gene duplication alleles, associated with ultrafast metabolizers, were found with frequencies of 0.005 (*1x2), 0.013 (*2x2), and 0.001 (*4x2).
Among 672 unrelated Europeans, Marez et al. (1997) identified 48 point mutations in the CYP2D6 gene, of which 29 were novel. Within the poor metabolizer group, the frequencies of the CYP2D6*4, CYP2D6*6, and CYP2D6*3 alleles were 65.8%, 6.2%, and 4.8%, respectively. The majority of the alleles occurred with a frequency of 0.1 to 2.7%.
The mean value of metabolic ratio for debrisoquine metabolism in an extensive metabolizer population was reported to be slightly higher in Asians than in Caucasians. This interethnic difference was assumed to be caused by the higher frequency of the CYP2D6*10 allele (124030.0005) in Asians (Johansson et al., 1994; Tateishi et al., 1999).
The occurrence of CYP2D6 gene duplication varies between populations. Among 217 white healthy Spaniards, Agundez et al. (1995) determined that the prevalence of multiple CYP2D6 copies was 7%. Aklillu et al. (1996) reported that 29% of Ethiopians carried extra CYP2D6 genes, whereas 1 to 2% of Swedish, German, Chinese, and black Zimbabwean populations had multiple copies. McLellan et al. (1997) found duplication of the CYP2D6 gene in 21 of 101 (21%) Saudi Arabians studied. In contrast, only 2 individuals were heterozygous for a deletion of the whole gene. The allele frequency of CYP2D6*4, the most common defective allele causing poor metabolism among Caucasians, was only 3.5% in the Saudi population. These findings were in agreement with earlier Saudi Arabian phenotyping studies that reported a low frequency (1 to 2%) of poor metabolizers for CYP2D6-probe drugs.
Among 60 Dutch individuals who were ultrarapid metabolizers of sparteine (metabolic ratio less than 0.15), Bathum et al. (1998) identified 9 with a duplicated CYP2D6 gene. The authors estimated a frequency of 0.8% for individuals with CYP2D6 duplication in the Danish population, which is comparable to the frequency in the Swedish and the German populations, but considerably lower than that in Spanish or African populations. Bathum et al. (1998) concluded that the long PCR assay is simple and reliable for detection of duplications of the CYP2D6 gene.
Based on their identification and characterization of a nonfunctional CYP2D7 gene and a CYP2D8 pseudogene, Kimura et al. (1989) suggested that gene duplication events gave rise to CYP2D6 and CYP2D7, and that gene conversion events occurred later to form CYP2D8. Kimura et al. (1989) suggested that these enzymes evolved to metabolize plant toxins; since current human diets rely almost totally on cultivation, while early man was a hunter-gatherer, the genes may now be in the process of being lost. Gene conversion events involving the closely linked and similar CYP2D7 and CYP2D8P genes may hasten this process.
Hanioka et al. (1990) isolated and completely sequenced a defective CYP2D7 gene and provided evidence that gene conversions have occurred between CYP2D6 and CYP2D7.
Heim and Meyer (1992) analyzed the arrangement and sequence of the CYP2D gene cluster variant (haplotype) containing a common allele of CYP2D6 found in poor metabolizers and associated with an XbaI 44-kb restriction fragment. This haplotype was found to contain the CYP2D6*4 variant (124030.0001) and 3 pseudogenes. Heim and Meyer (1992) postulated that a gene duplication of a CYP2D6-like gene occurred about 18 million years ago, generating a functional CYP2D8 gene that later became a pseudogene. About 9 million years ago, a similar duplication event yielded the CYP2D7 gene. About 1 to 2 million years ago, unequal crossover events and gene conversion events may have yielded the CYP2D6*4 mutation, which is found in the majority of mutant alleles. Since poor metabolizers have no reproductive advantage, the CYP2D6 gene may also eventually become a pseudogene. Heim and Meyer (1992) noted that the ancestors of these drug metabolizing enzymes were developed in animals who ingested plants and plant toxins. The plants defended themselves by developing new toxins, and the animals developed new P450s able to detoxify these new toxins.
Nebert (1997) reviewed the field of drug-metabolizing enzymes (DMEs) and DME-receptor research and how DMEs have evolved through animal-plant interactions.
Steen et al. (1995) identified a 2.8-kb repeated region (CYP-REP) that flanks the active CYP2D6 gene and may have played a role in deletion (124030.0002) and amplification of CYP2D6.
Lundqvist et al. (1999) presented evidence that CYP2D6 gene duplications occurred through unequal crossover at a breakpoint in the 3-prime flanking region of the CYP2D6*2B allele with a specific repetitive sequence. Alleles with 13 copies of the gene were likely formed by unequal segregation and extrachromosomal replication of acentric DNA. Lundqvist et al. (1999) suggested that the high frequencies of multiduplicated genes in Saudi Arabian and Ethiopian populations indicated that a dietary selective pressure existed in those regions in the past. These variants may have been introduced into the Spanish population during the Muslim migration.
Based on recommendations for human genome nomenclature, Daly et al. (1996) proposed that alleles at this locus be designated by CYP2D6 followed by an asterisk and a combination of roman letters and arabic numerals distinct for each allele, with the number specifying the key mutation and, where appropriate, a letter specifying additional mutations. See also nomenclature recommendations presented by Nelson et al. (1996), Nebert et al. (1987), and Nelson et al. (2004).
Matsunaga et al. (1989) studied the DA rat, which has impaired ability to metabolize debrisoquine and therefore may be useful as a model of the human genetic defect in debrisoquine metabolism.
This allelic variant is also known as CYP2D6*4 or CYP2D6(B).
In 20 individuals with poor metabolism of debrisoquine (608902), Gough et al. (1990) identified a G-to-A transition at the first nucleotide of exon 4 in the CYP2D6 gene, resulting in a shift of the splice site and introduction of a premature termination codon. The mutant protein had no residual activity. Gough et al. (1990) presented preliminary data suggesting a reduction in the proportion of poor metabolizers among patients with lung or bladder cancer.
In leukocyte DNA of an individual who was deficient in debrisoquine metabolism, Hanioka et al. (1990) identified a 1934G-A transition at the junction of the third intron and fourth exon, resulting in an aberrant 3-prime splice recognition site and an mRNA with a single basepair deletion. The disrupted mRNA leads to a truncated protein without functional activity. The patient studied was a compound heterozygote: the allele with the 1934G-A mutation was identified by a 44-kb XbaI restriction fragment; the second allele was a complete deletion of the CYP2D6 gene (124030.0002). The dextromethorphan urinary metabolite ratio in this patient was 9.7, which is operationally defined as a poor metabolizer of debrisoquine.
Kagimoto et al. (1990) likewise concluded that the mutation at the 3-prime splice site of intron 3 is a common cause of the poor metabolizer phenotype.
Chen et al. (1995) found that Alzheimer disease (104300) patients who were either heterozygous or homozygous for the CYP2D6*4 allele had a smaller decline of the synaptic markers choline acetyltransferase (118490) and synaptophysin (313475) in the frontal cortex than those who did not. Senile plaques neurofibrillary tangles were not significantly affected. The authors had earlier shown an association of the CYP2D6*4 mutant allele with Lewy body formation (127750). The findings suggested different mechanisms of neurodegeneration in the 2 disorders.
This allelic variant is also known as CYP2D6*5 and CYP2D6(D).
In 1 of 42 poor metabolizer individuals (608902), Gough et al. (1990) found homozygous deletion of the CYP2D locus. In a poor metabolizer, Gaedigk et al. (1991) identified a homozygous 11.5-kb deletion associated with deletion of the entire CYP2D6 gene and total absence of P4502D6 protein in the liver.
Steen et al. (1995) identified a 2.8-kb repeated region (CYP-REP) that flanks the active CYP2D6 gene and contains the breakpoints involved in the generation of CYP2D6*5. Steen et al. (1995) proposed that the deletion mechanism involved unequal recombination between 2 homologous but nonallelic sequences, either by chromosome misalignment followed by unequal crossover or by the formation of a loop structure on a single chromosome. The deleted region spans 12.1 kb.
Idle et al. (2000) pointed out that the copy of chromosome 22 sequenced by the Human Genome Project has the CYP2D6*5 deletion allele, i.e., does not contain the CYP2D6 gene. The CYP2D6*5 allele, a deletion that includes the entire CYP2D6 gene, is the second most common inactivating allele in the U.K. population. Nelson et al. (2004) reported that the frequency of the CYP2D6*5 allele was 0.04 in Caucasian populations. Idle et al. (2000) suggested that other genes of medical import may be missed by the Human Genome Project because 'nature has chosen to delete them on one of our pair of chromosomes, as was the case with CYP2D6.'
This allelic variant is also known as CYP2D6*6 or CYP2D6(T).
In individuals with the PM phenotype (608902), Saxena et al. (1994) identified a single base deletion in exon 3 of the CYP2D6 gene, removing thymine-1795 and resulting in a premature stop codon. They designated the allele CYP2D6(T). Among Caucasian controls, the frequency of the 2D6(T) allele was 1.8% (4/220 chromosomes).
In a Caucasian patient with deficiency of the CYP2D6 enzyme and poor metabolism (608902), Broly et al. (1995) identified a gly169-to-ter (G169X) mutation in exon 3 of the CYP2D6 gene.
This allelic variant is also known as CYP2D6*10 or CYP2D6(J) or CYP2D6(Ch1, Ch2).
Kagimoto et al. (1990) identified a 188C-T transition in exon 1 of the CYP2D6 gene, resulting in a pro34-to-ser (P34S) substitution as a cause of the debrisoquine poor metabolizer phenotype (608902). Nakamura et al. (2002) presented data strongly suggesting that catalytic activity as well thermal stability of the enzyme is affected by the P34S polymorphism. They proposed that thermal instability together with reduced intrinsic clearance of CYP2D6*10 is one reason for the finding of lower metabolic activities for drugs metabolized by CYP2D6 in Asians, who have a high frequency of CYP2D6*10, compared with Caucasians.
This allelic variant is also known as CYP2D6*3 or CYP2D6(A).
Marez et al. (1997) identified a 1-bp deletion (2637A) in exon 5 of the CYP2D6 gene in a group of individuals with the poor metabolizer phenotype (608902).
This allelic variant is also known as CYP2D6*2 or CYP2D6L.
In a family in which 2 sibs and their father had MRs of less that 0.02 (ultrarapid phenotype, see 608902), Johansson et al. (1993) found 12 extra copies of the CYP2D6 gene inherited in an autosomal dominant pattern; in a second family in which 2 sibs had MRs of less than 0.1, the authors found 2 extra copies of the CYP2D6 gene. All affected individuals had a variant CYP2D6 gene, termed CYP2D6L, which contained 2 amino acid substitutions: a 2938C-T transition in exon 6, resulting in an arg296-to-cys (R296C), and a 4268G-to-C transversion in exon 9, resulting in a resulting in a ser486-to-thr (S486T) substitution. The MR of individuals with 1 copy of the CYP2D6L gene did not differ from those with the wildtype gene, but there was a correlation between decreased MR and increased copies of the CYP2D6L gene.
Panserat et al. (1994) identified the R296C and S486T changes as 2 major CYP2D6 allozymes in extensive metabolizers (wildtype). Residue 296 falls within a presumed substrate recognition site, and residue 486 lies in the vicinity of the heme binding site.
Gasche et al. (2004) described a patient who had developed life-threatening opioid intoxication after he was given small doses of codeine for the treatment of cough associated with bilateral pneumonia. CYP2D6 genotyping showed 3 or more functioning alleles, as a result of gene duplication, resulting in high levels of morphine and morphine-6 glucuronide. Reduction in CYP3A4 (124010) activity by other medications and acute renal failure causing glucuronide accumulation were also factors in the codeine toxicity. Codeine is ineffective at usual doses in 7 to 10% of the white population because of homozygosity for nonfunctional mutant CYP2D6 alleles (Desmeules et al., 1991). The concentration of O-demethylated metabolites can be as much as 45 times as high in persons with ultrarapid CYP2D6 metabolism (see 608902) as it is in those with poor metabolism (Yue et al., 1997).
Koren et al. (2006) reported an infant boy who showed intermittent periods of difficulty in breastfeeding and lethargy beginning at day 7, and later was noted to have gray skin. He died on day 13. The mother had been taking codeine for episiotomy pain, and the infant was found to have high serum levels of morphine. Genotype analysis showed that the mother carried the CYP2D6 duplication and was an ultrarapid metabolizer of codeine, resulting in increased formation of morphine from codeine. The morphine was transferred to the baby through breast milk, resulting in opioid toxicity and neonatal death. Koren et al. (2006) concluded that maternal codeine use should not be considered safe for all infants during breastfeeding.
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