Terfenadine metabolism of human cytochrome P450 2J2 containing genetic variations (G312R, P351L and P115L)

Jeong, Dabin; Park, Hyoung-Goo; Lim, Young-Ran; Lee, Yejin; Kim, Vitchan; Cho, Myung-A.; Kim, Donghak

doi:10.1016/j.dmpk.2017.10.004

Cited by 11 publications

(20 citation statements)

References 24 publications

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“…For terfenadine (M9), experimental results showed that two variants of CYP2J2, P351L and P115L, had similar enzyme activity for t-butyl methyl hydroxylation to the wild-type CYP2J2 45 . Based on the present docking result, P351 and P115 were not involved in the interactions with terfenadine, and thus could have little effect on the metabolism of terfenadine.…”

Section: M1-m3mentioning

confidence: 99%

“…Based on the present docking result, P351 and P115 were not involved in the interactions with terfenadine, and thus could have little effect on the metabolism of terfenadine. In addition, the G312R variant was implied to destabilize the structure of CYP2J2 by altering the heme environment 45 , and cause the loss of the catalytic activity of CYP2J2 46 . The same effect was also observed in the present CYP2J2 model, as Gly312 was near the active site and the introduction of Arg would significantly change the electrostatic potential around the heme, and consequently impair the enzyme catalytic activity and structural stability.…”

Section: M1-m3mentioning

confidence: 99%

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Molecular determinant of substrate binding and specificity of cytochrome P450 2J2

Chen

2020

Sci Rep

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Cytochrome P450 2J2 (CYP2J2) is responsible for the epoxidation of endogenous arachidonic acid, and is involved in the metabolism of exogenous drugs. To date, no crystal structure of CYP2J2 is available, and the proposed structural basis for the substrate recognition and specificity in CYP2J2 varies with the structural models developed using different computational protocols. In this study, we developed a new structural model of CYP2J2, and explored its sensitivity to substrate binding by molecular dynamics simulations of the interactions with chemically similar fluorescent probes. Our results showed that the induced-fit binding of these probes led to the preferred active poses ready for the catalysis by CYP2J2. Divergent conformational dynamics of CYP2J2 due to the binding of each probe were observed. However, a stable hydrophobic clamp composed of residues I127, F310, A311, V380, and I487 was identified to restrict any substrate access to the active site of CYP2J2. Molecular docking of a series of compounds including amiodarone, astemizole, danazol, ebastine, ketoconazole, terfenadine, terfenadone, and arachidonic acid to CYP2J2 confirmed the role of those residues in determining substrate binding and specificity of CYP2J2. In addition to the flexibility of CYP2J2, the present work also identified other factors such as electrostatic potential in the vicinity of the active site, and substrate strain energy and property that have implications for the interpretation of CYP2J2 metabolism.

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Section: M1-m3mentioning

confidence: 99%

Section: M1-m3mentioning

confidence: 99%

Molecular determinant of substrate binding and specificity of cytochrome P450 2J2

Chen

2020

Sci Rep

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“…P450 2C9 wild type and its allelic variants were expressed as previously described, with minor modifications (Jeong et al ., 2018; Lee et al ., 2018). The pCW vectors for the P450 2C9 variants were transformed into the E. coli DH5α strain.…”

Section: Methodsmentioning

confidence: 99%

“…In particular, polymorphisms in human P450 enzymes can affect catalytic activity. Therefore, the metabolic outcomes of P450 genetic variants can have pharmacological and toxicological impacts on the therapeutic drugs (Lee and Kim, 2011; Jeong et al ., 2018; Kim et al ., 2018). Oscarson has supported the systematic nomenclature of the human P450 alleles (https://www.pharmvar.org/).…”

Section: Introductionmentioning

confidence: 99%

Functional Characterization of Pharmcogenetic Variants of Human Cytochrome P450 2C9 in Korean Populations

Cho

Yoon

Kim

et al. 2019

Biomolecules & Therapeutics

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Human cytochrome P450 2C9 is a highly polymorphic enzyme that is required for drug and xenobiotic metabolism. Here, we studied eleven P450 2C9 genetic variants—including three novel variants F69S, L310V, and Q324X—that were clinically identified in Korean patients. P450 2C9 variant enzymes were expressed in Escherichia coli and their bicistronic membrane fractions were prepared The CO-binding spectra were obtained for nine enzyme variants, indicating P450 holoenzymes, but not for the M02 (L90P) variant. The M11 (Q324X) variant could not be expressed due to an early nonsense mutation. LC-MS/MS analysis was performed to measure the catalytic activities of the P450 2C9 variants, using diclofenac as a substrate. Steady-state kinetic analysis revealed that the catalytic efficiency of all nine P450 2C9 variants was lower than that of the wild type P450 2C9 enzyme. The M05 (R150L) and M06 (P279T) variants showed high kcat values; however, their Km values were also high. As the M01 (F69S), M03 (R124Q), M04 (R125H), M08 (I359L), M09 (I359T), and M10 (A477T) variants exhibited higher Km and lower kcat values than that of the wild type enzyme, their catalytic efficiency decreased by approximately 50-fold compared to the wild type enzyme. Furthermore, the novel variant M07 (L310V) showed lower kcat and Km values than the wild type enzyme, which resulted in its decreased (80%) catalytic efficiency. The X-ray crystal structure of P450 2C9 revealed the presence of mutations in the residues surrounding the substrate-binding cavity. Functional characterization of these genetic variants can help understand the pharmacogenetic outcomes.

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“…FEX is an active metabolite of TER formed in vivo by transforming the tert -butyl to the carboxylate group under the influence of the enzyme CYP3A4 (Figure 1(a)). On the contrary to TER, FEX provides a sufficient balance between efficacy and safety for the cardiovascular system and is widely used for the treatment of allergy symptoms [4, 5].…”

Section: Introductionmentioning

confidence: 99%

Comparative Study of Chemical Stability of Two H₁Antihistaminic Drugs, Terfenadine and ItsIn VivoMetabolite Fexofenadine, Using LC-UV Methods

Gumieniczek

Berecka‐Rycerz

Pietraś

et al. 2019

Journal of Analytical Methods in Chemistry

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A comparative study of chemical stability of terfenadine (TER) and its in vivo metabolite fexofenadine (FEX) was performed. Both TER and FEX were subjected to high temperature at different pH and UV/VIS light at different pH and then quantitatively analyzed using new validated LC-UV methods. These methods were used to monitor the degradation processes and to determine the kinetics of degradation for both the compounds. As far as the effects of temperature and pH were concerned, FEX occurred more sensitive to degradation than TER. As far as the effects of UV/VIS light and pH were concerned, the both drugs were similarly sensitive to high doses of light. Using all stress conditions, the processes of degradation of TER and FEX followed the first-order kinetics. The results obtained for these two antihistaminic drugs could be helpful in developing their new derivatives with higher activity and stability at the same time.

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Terfenadine metabolism of human cytochrome P450 2J2 containing genetic variations (G312R, P351L and P115L)

Cited by 11 publications

References 24 publications

Molecular determinant of substrate binding and specificity of cytochrome P450 2J2

Molecular determinant of substrate binding and specificity of cytochrome P450 2J2

Functional Characterization of Pharmcogenetic Variants of Human Cytochrome P450 2C9 in Korean Populations

Comparative Study of Chemical Stability of Two H₁Antihistaminic Drugs, Terfenadine and ItsIn VivoMetabolite Fexofenadine, Using LC-UV Methods

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Terfenadine metabolism of human cytochrome P450 2J2 containing genetic variations (G312R, P351L and P115L)

Cited by 11 publications

References 24 publications

Molecular determinant of substrate binding and specificity of cytochrome P450 2J2

Molecular determinant of substrate binding and specificity of cytochrome P450 2J2

Functional Characterization of Pharmcogenetic Variants of Human Cytochrome P450 2C9 in Korean Populations

Comparative Study of Chemical Stability of Two H1Antihistaminic Drugs, Terfenadine and ItsIn VivoMetabolite Fexofenadine, Using LC-UV Methods

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Comparative Study of Chemical Stability of Two H₁Antihistaminic Drugs, Terfenadine and ItsIn VivoMetabolite Fexofenadine, Using LC-UV Methods