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190) The reduced carbon monoxide-difference spectra of wild-type CYP3A4 and 31 CYP3A4 variants produced with our established mammalian cell expression system were determined by measuring the increase in maximum absorption at 450 nm after carbon monoxide treatment.
2021 Drug metabolism and disposition: the biological fate of chemicals
* Functional Characterization of 40 CYP3A4 Variants by Assessing Midazolam 1'-Hydroxylation and Testosterone 6β-Hydroxylation.
- CYP3A4 is among the most abundant liver and intestinal drug-metabolizing cytochrome P450 enzymes, contributing to the metabolism of more than 30% of clinically used drugs. Therefore, interindividual variability in CYP3A4 activity is a frequent cause of reduced drug efficacy and adverse effects. In this study, we characterized wild-type CYP3A4 and 40 CYP3A4 variants, including 11 new variants, detected among 4773 Japanese individuals by assessing CYP3A4 enzymatic activities for two representative substrates (midazolam and testosterone). The reduced carbon monoxide-difference spectra of wild-type CYP3A4 and 31 CYP3A4 variants produced with our established mammalian cell expression system were determined by measuring the increase in maximum absorption at 450 nm after carbon monoxide treatment. The kinetic parameters of midazolam and testosterone hydroxylation by wild-type CYP3A4 and 29 CYP3A4 variants (Km , kcat , and catalytic efficiency) were determined, and the causes of their kinetic differences were evaluated by three-dimensional structural modeling. Our findings offer insight into the mechanism underlying interindividual differences in CYP3A4-dependent drug metabolism. Moreover, our results provide guidance for improving drug administration protocols by considering the information on CYP3A4 genetic polymorphisms. SIGNIFICANCE STATEMENT: CYP3A4 metabolizes more than 30% of clinically used drugs. Interindividual differences in drug efficacy and adverse-effect rates have been linked to ethnicity-specific differences in CYP3A4 gene variants in Asian populations, including Japanese individuals, indicating the presence of CYP3A4 polymorphisms resulting in the increased expression of loss-of-function variants. This study detected alterations in CYP3A4 activity due to amino acid substitutions by assessing the enzymatic activities of coding variants for two representative CYP3A4 substrates.
=>貧しい暮らし, 落ちぶれた生活
Overview of verb reduce
The verb reduce has 20 senses (first 11 from tagged texts)
1. (102) reduce, cut down, cut back, trim, trim down, trim back, cut, bring down -- (cut down on;
make a reduction in; "reduce your daily fat intake"; "The employer wants to cut back health
benefits")
2. (9) reduce -- (make less complex; "reduce a problem to a single question")
3. (5) reduce -- (bring to humbler or weaker state or condition; "He reduced the population to
slavery")
4. (3) reduce -- (simplify the form of a mathematical equation of expression by substituting one
term for another)
5. (3) reduce -- (lower in grade or rank or force somebody into an undignified situation; "She
reduced her niece to a servant")
6. (3) reduce, come down, boil down -- (be the essential element; "The proposal boils down to a
compromise")
7. (2) shrink, reduce -- (reduce in size; reduce physically; "Hot water will shrink the sweater";
"Can you shrink this image?")
8. (1) reduce -- (lessen and make more modest; "reduce one's standard of living")
9. (1) reduce, scale down -- (make smaller; "reduce an image")
10. (1) deoxidize, deoxidise, reduce -- (to remove oxygen from a compound, or cause to react with
hydrogen or form a hydride, or to undergo an increase in the number of electrons)
11. (1) reduce, tighten -- (narrow or limit; "reduce the influx of foreigners")
12. repress, quash, keep down, subdue, subjugate, reduce -- (put down by force or intimidation; "The
government quashes any attempt of an uprising"; "China keeps down her dissidents very efficiently";
"The rich landowners subjugated the peasants working the land")
13. reduce -- (undergo meiosis; "The cells reduce")
14. reduce -- (reposition (a broken bone after surgery) back to its normal site)
15. reduce -- (destress and thus weaken a sound when pronouncing it)
16. abridge, foreshorten, abbreviate, shorten, cut, contract, reduce -- (reduce in scope while
retaining essential elements; "The manuscript must be shortened")
17. boil down, reduce, decoct, concentrate -- (be cooked until very little liquid is left; "The
sauce should reduce to one cup")
18. reduce, boil down, concentrate -- (cook until very little liquid is left; "The cook reduced the
sauce by boiling it for a long time")
19. dilute, thin, thin out, reduce, cut -- (lessen the strength or flavor of a solution or mixture;
"cut bourbon")
20. reduce, melt off, lose weight, slim, slenderize, thin, slim down -- (take off weight)
Overview of adj reduced
The adj reduced has 2 senses (first 2 from tagged texts)
1. (6) decreased, reduced -- (made less in size or amount or degree)
2. (1) reduced, rock-bottom -- (well below normal (especially in price))
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