Functional Significance of Cytochrome P450 1A2 Allelic Variants, P450 1A2*8, *15, and *16 (R456H, P42R, and R377Q)

Biomolecules & Therapeutics
Young-Ran LimDonghak Kim

Abstract

P450 1A2 is responsible for the metabolism of clinically important drugs and the metabolic activation of environmental chemicals. Genetic variations of P450 1A2 can influence its ability to perform these functions, and thus, this study aimed to characterize the functional significance of three P450 1A2 allelic variants containing nonsynonymous single nucleotide polymorphisms (P450 1A2*8, R456H; *15, P42R; *16, R377Q). Variants containing these SNPs were constructed and the recombinant enzymes were expressed and purified in Escherichia coli. Only the P42R variant displayed the typical CO-binding spectrum indicating a P450 holoenzyme with an expression level of ∼ 170 nmol per liter culture, but no P450 spectra were observed for the two other variants. Western blot analysis revealed that the level of expression for the P42R variant was lower than that of the wild type, however the expression of variants R456H and R377Q was not detected. Enzyme kinetic analyses indicated that the P42R mutation in P450 1A2 resulted in significant changes in catalytic activities. The P42R variant displayed an increased catalytic turnover numbers (k cat) in both of methoxyresorufin O-demethylation and phenacetin O-deethylation. In the case of phenacet...Continue Reading

References

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Mar 3, 2004·Molecular Interventions·F Peter Guengerich
Mar 17, 2005·Drug Metabolism and Pharmacokinetics·Akiko SoyamaJun-ichi Sawada
Apr 12, 2005·Annual Review of Pharmacology and Toxicology·Donghak Kim, F Peter Guengerich
Oct 7, 2005·The Journal of Biological Chemistry·Donghak KimF Peter Guengerich
Feb 22, 2007·The Journal of Biological Chemistry·Stefaan SansenEric F Johnson
Dec 6, 2011·Archives of Pharmacal Research·Im-Soon Lee, Donghak Kim
Jan 10, 2014·Biomolecules & Therapeutics·Seunghye ChoiDonghak Kim
May 6, 2014·Toxicological Research·Hyoung-Goo ParkDonghak Kim

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Citations

Oct 30, 2016·Drug Metabolism and Pharmacokinetics·Songhee HanChul-Ho Yun

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