Abstract
Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin O-deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants.
Highlights
The individual impact and clinical significance of genetic factors on drug metabolism have been well established in vivo and in vitro [1,2,3,4,5]
The enzymatic activities of 21 novel Cytochrome P450 1A2 (CYP1A2) variants expressed in 293FT cells were characterized by their ability to catalyze phenacetin O-deethylation
A majority of the evaluated variants (90%) showed either decreased or negligible enzymatic activity. Patients harboring these rare genetic variants could be at higher risk of compromised treatment outcomes or experience increased risk from exposure to CYP1A2-inducing environmental factors
Summary
The individual impact and clinical significance of genetic factors on drug metabolism have been well established in vivo and in vitro [1,2,3,4,5]. The drug-metabolizing enzyme cytochrome P450 1A2 (CYP1A2) is constitutively expressed in the human liver and accounts for approximately 13% of the total hepatic cytochrome (CYP) content [8,9]. It catalyzes the metabolism of approximately 9% of commonly used drugs, including the oxidation of drugs such as theophylline, olanzapine, and propranolol [10,11]. 40 polymorphic variants of the CYP1A2 gene have been reported (https://www.pharmvar.org/gene/CYP1A2 accessed on 21 July 2021), of which the most frequent and most highly characterized variant is the -163C>A polymorphism (CYP1A2*1F), located in the promoter region. Examples include a report of decreased blood levels of olanzapine in schizophrenic patients with the -163C>A polymorphism, and one discussing increased clearance of theophylline in non-smoker asthmatic patients carrying the -3860C>A polymorphism [15,16]
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