CYP2D6 enzyme activity

Eq. 3 AGbind, free energy of binding Mr, relative molecular mass Null, number of active site hydrogen bonds formed between substrate and human CYP2D6 N% number of K-K stacking interactions formed between substrate and enzyme active sites. 

The biochemical basis for the trait is an almost complete absence of one form of cytochrome P-450, CYP2D6. It seems that there are several mutations, which give rise to the poor metabolizer phenotype. These mutations produce incorrectly spliced, variant mRNAs in the liver from poor metabolizers. At least three mutant alleles have been described for the CYP2D6 gene and in those with "poor metabolizer" status. A large number of mutations have also been described some of which, but not all, affect enzyme activity. However, for some of... 

Second, there are often different variants in different populations some phenotypic consequences of CYP2D6 variations are shown as an example in Figure 2 (1). There is a lower average enzyme activity in both, Chinese and Africans, in comparison to that in Europeans. These differences in activity represent structural changes of the CYP2D6 protein that affect enzyme function. However, the enzyme structures that cause the lower activities are different in the Chinese (13) and in the African populations (14). It is an independent fact that enzyme absence is more rare in Asians and Africans than in Europeans (4). 

Mutations in CYP2D6 (25) may lead to three kinds of functional changes absence, decrease, or increase of enzyme activity. Lack of enzyme activity indicates in most cases a frameshift mutation or a splicing defect, but there is also a case of totally missing enzyme formation. Decreases of enzyme activity indicate a change of enzyme structure these can be clinically treacherous since the decrease may differ in severity for different sustrates. Enhanced enzyme activity indicates usually gene duplication, sometimes multiplication a case of 13-fold multiplication has been observed. Everyone of these enzyme changes may differ between human populations. 

Many African data were due to the variant CYP2D6 17 which has reduced activity. This variant occurred with an allele frequency of 37% in Zimbabwe, of 17% in Tanzania, and in 9% in Ethiopia (8). The reduced enzyme activity in Asia is due to a different variant, CYP2D6 10 characterized by C188T, which has in China a frequency of 51%. Besides their generally reduced activity, the Asian and African variants have no similarity. The activities of these variants towards different substrates requires much additional investigation. 

Actually, CY2D6 gene polymorphisms, associated with null or reduced enzyme activity, have been reported to negatively influence (in a gene-dose manner) the blood level of endoxifen in numerous prospective pharmacokinetic studies [11,172, 192-196], Some retrospective and prospective studies have shown that CYP2D6 polymorphism was associated with worse clinical outcomes in PMs and IMs patients in terms of recurrence and disease free survival or BC development in the chemo-prevention setting [192,194,195,197-205],... 

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