Molecular heterogeneity of the XbaI defined 44kb allele of the CYP2D locus within the Caucasian population.

1. Cytochrome P450 debrisoquine (CYP2D6) activity is polymorphic and under genetic control. Most Caucasians are extensive metabolizers, but 5%-10% are poor metabolizers. 2. Restriction fragment length polymorphism analysis of the CYP2D6 locus identifies a 29kb XbaI fragment, either normal (D6-wt) or mutated, and three mutated XbaI alleles (44kb, 11.5kb and 16 + 9kb). The 44kb allele was initially considered as a poor metabolizer allele owing to a D6-B mutation, but cases of 44kb allele not carrying the D6-B, and therefore potentially functional, have been found. The degree of molecular heterogeneity of this allele was investigated by phenotype and genotype analysis of families. 3. Thirty-one French Caucasian families, representing 117 individuals, possessing at least one 44kb allele in each family were selected. Phenotypes were determined using dextromethorphan, and the XbaI, NcoI and BamH1 RFLPs of 42 independent chromosomes were analyzed. 4. 80% of the XbaI 44kb alleles carried the CYP2D6-B mutation and had an additional NcoI fragment (12.5kb or 4.8kb). The remaining 20% did not carry the CYP2D6-B or A mutations and had no extra NcoI fragment. 5. Information on three families demonstrated that 44kb alleles not carrying the CYP2D6-B mutation were associated with the extensive metabolizer phenotype. 6. We conclude that a substantial percentage of XbaI 44kb alleles is associated with a functional CYP2D gene, and therefore, that the XbaI 44kb allele is not consistently a poor metaboliser allele.