Which CYP (Cytochrome P450) enzyme are African-Americans poor metabolizers of?

CYP2D6 is the Primary CYP Enzyme That African-Americans are Poor Metabolizers Of

African-Americans have a significantly higher prevalence of the CYP2D6*17 allele, which results in reduced CYP2D6 enzyme function and classifies them as poor metabolizers of this enzyme.

Genetic Basis of CYP2D6 Metabolism in African-Americans

The metabolism of many medications is significantly affected by genetic polymorphisms in the Cytochrome P450 (CYP450) family of enzymes. For African-Americans specifically, CYP2D6 shows the most clinically significant variation:

• African-Americans demonstrate significantly lower CYP2D6 activity compared to white populations, with median urinary dextromethorphan/dextrorphan metabolic ratios showing reduced function 1
• The CYP2D6*17 allele occurs at a frequency of 0.213 in African-Americans and is particularly concentrated in those with intermediate metabolizer status 1
• The CYP2D6*29 allele (frequency of 0.072) also contributes to reduced function in this population 1

Clinical Significance of CYP2D6 Poor Metabolism

Poor CYP2D6 metabolism has significant implications for medication efficacy and safety:

1. Medications affected by CYP2D6 metabolism include:

   • Tricyclic antidepressants
   • Selective serotonin reuptake inhibitors (particularly paroxetine and fluoxetine)
   • "Third-generation" antidepressants (venlafaxine and mirtazapine)
   • Codeine and other opioids requiring conversion to active metabolites 2

2. Clinical consequences:

   • Poor metabolizers have higher risk of adverse effects with standard doses of CYP2D6 substrates 2
   • Codeine is particularly problematic as it's a prodrug requiring CYP2D6 metabolism to convert to morphine - poor metabolizers will experience reduced analgesic effects 2
   • Duloxetine levels can be significantly higher in CYP2D6 poor metabolizers, requiring lower starting doses 3

Ethnic Distribution of CYP2D6 Polymorphisms

The distribution of CYP2D6 metabolizer phenotypes varies significantly across ethnic groups:

• Poor metabolizer status occurs in:

  • 5-10% of Caucasians
  • 0-2% of Asians
  • 1.9-7.25% of African-Americans (with variation across studies) 4, 1, 5

• The reduced function CYP2D6*17 allele is particularly prevalent in African-Americans:

  • Found in 39.5% of intermediate metabolizers vs 14.8% of extensive metabolizers 1
  • Overall frequency of 21.3% in African-American populations 1

Clinical Implications and Recommendations

The unique distribution of CYP2D6 alleles in African-Americans has important clinical implications:

1. For medications metabolized by CYP2D6:

   • Consider potential for reduced metabolism in African-American patients
   • Monitor more closely for adverse effects with standard doses
   • Consider starting with lower doses of medications heavily dependent on CYP2D6 metabolism

2. For prodrugs requiring CYP2D6 activation (like codeine):

   • Be aware that African-Americans may experience reduced efficacy
   • Consider alternative analgesics not dependent on CYP2D6 activation

3. For pharmacogenetic testing:

   • Standard CYP2D6 testing must include the *17 allele to accurately assess African-American patients 6
   • Nucleotide arrays or similar comprehensive methods are needed to efficiently test for the most relevant CYP2D6 alleles in diverse populations 6

While the prevalence of poor metabolizer status is lower in African-Americans than in Caucasians, the higher frequency of reduced function alleles like CYP2D6*17 results in an overall lower CYP2D6 activity that can significantly impact drug response and safety.