ELIZA

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321496 occurrences (No.66 in the rank) during 5 years in the PubMed. [no cache] 500 found

184) Alaska Native people are under-represented in genetic research but have unique gene variation that may critically impact their response to pharmacotherapy.

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PMID:33632714 DOI:10.1124/dmd.120.000301

2021 Drug metabolism and disposition: the biological fate of chemicals

* In Vivo Functional Effects of CYP2C9 M1L, a Novel and Common Variant in the Yup'ik Alaska Native Population.

- Alaska Native people are under-represented in genetic research but have unique gene variation that may critically impact their response to pharmacotherapy. Full resequencing of CYP2C9 in a cross-section of this population identified CYP2C9 Met1Leu (M1L), a novel, relatively common single nucleotide polymorphism hypothesized to confer CYP2C9 poor metabolizer phenotype by disrupting the start codon. M1L is present at a minor allele frequency of 6.3% in Yup'ik Alaska Native people and thus can contribute to the risk of an adverse drug response from narrow-therapeutic-index CYP2C9 substrates such as (S)-warfarin. This study's objective was to characterize the catalytic efficiency of the Leu1 variant enzyme in vivo by evaluating the pharmacokinetic behavior of naproxen, a probe substrate for CYP2C9 activity, in genotyped Yup'ik participants. We first confirmed the selectivity of (S)-naproxen O-demethylation by CYP2C9 using activity-phenotyped human liver microsomes and selective cytochrome P450 inhibitors and then developed and validated a novel liquid chromatography mass spectrometry method for simultaneous quantification of (S)-naproxen, (S)-O-desmethylnaproxen, and naproxen acyl glucuronide in human urine. The average ratio of (S)-O-desmethylnaproxen to unchanged (S)-naproxen in urine was 18.0 ± 8.0 (n = 11) for the homozygous CYP2C9Met1 reference group and 10.3 ± 6.6 (n = 11) for the Leu1 variant carrier group (P = 0.011). The effect of M1L variation on CYP2C9 function and its potential to alter the pharmacokinetics of drugs metabolized by the enzyme has clinical implications and should be included in a variant screening panel when pharmacogenetic testing in the Alaska Native population is warranted. SIGNIFICANCE STATEMENT: The novel CYP2C9 Met1Leu variant in Alaska Native people was recently identified. This study validated (S)-naproxen as a CYP2C9 probe substrate to characterize the in vivo functional activity of the CYP2C9 Leu1 variant. The results of this pharmacogenetic-pharmacokinetic study suggest that the CYP2C9 Leu1 variant exhibits loss of enzyme activity. This finding may be important to consider when administering narrow-therapeutic-index medications metabolized by CYP2C9 and also compels further investigation to characterize novel genetic variation in understudied populations.

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(1)136 the	(18)4 oxidative	(35)2 Nanotechnology	(52)2 medical
(2)13 different	(19)4 physiological	(36)2 RNA	(53)2 montelukast
(3)10 a	(20)4 six	(37)2 SD,	(54)2 nanoconfinement
(4)8 null	(21)4 study	(38)2 anaerobic	(55)2 nutritional
(5)7 investigation	(22)3 acidic	(39)2 anesthesia	(56)2 other
(6)7 of	(23)3 and	(40)2 certain	(57)2 our
(7)6 in	(24)3 basal	(41)2 common	(58)2 real
(8)6 normal	(25)3 conditions	(42)2 curve	(59)2 real-world
(9)6 these	(26)3 control	(43)2 each	(60)2 this
(10)5 an	(27)3 development	(44)2 endoscopic	(61)2 three
(11)5 both	(28)3 high	(45)2 ex	(62)2 treatment
(12)5 which	(29)3 inverted	(46)2 fasted	(63)2 two
(13)4 assessment	(30)3 some	(47)2 five	(64)2 typical
(14)4 clinical	(31)3 various	(48)2 four	(65)2 water-deficit
(15)4 controlled	(32)3 water	(49)2 hypoxia
(16)4 general	(33)2 18	(50)2 intense
(17)4 hypoxic	(34)2 808	(51)2 low

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--- WordNet output for under --- =>以下の, (治療, 試練, 刑罰)を受けて, 下部の, の下に, ・・の下に Overview of adj under The adj under has 2 senses (first 2 from tagged texts) 1. (2) nether, under -- (located below or beneath something else; "nether garments"; "the under parts of a machine") 2. (1) under -- (lower in rank, power, or authority; "an under secretary") Overview of adv under The adv under has 8 senses (first 1 from tagged texts) 1. (2) under -- (down to defeat, death, or ruin; "their competitors went under") 2. under -- (through a range downward; "children six and under will be admitted free") 3. under -- (into unconsciousness; "this will put the patient under") 4. under -- (in or into a state of subordination or subjugation; "we must keep our disappointment under") 5. under -- (below some quantity or limit; "fifty dollars or under") 6. under -- (below the horizon; "the sun went under") 7. under -- (down below; "get under quickly!") 8. under, below -- (further down; "see under for further discussion") --- WordNet end ---