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286534 occurrences (No.87 in the rank) during 5 years in the PubMed. [no cache] 500 found

33) In conclusion, we demonstrated that MSRA expressed in tissues is involved in sulindac activation, making a larger contribution than the gut microbiota.

--- ABSTRACT ---

PMID:35279645 DOI:10.1124/dmd.122.000828

2021 Drug metabolism and disposition: the biological fate of chemicals

* Methionine Sulfoxide Reductase A in Human and Mouse Tissues is Responsible for Sulindac Activation, Making a Larger Contribution than the Gut Microbiota.

- Sulindac is a nonsteroidal anti-inflammatory prodrug that is converted to its pharmacologically active metabolite, sulindac sulfide, via a reduction reaction. It is widely accepted that the gut microbiota is responsible for sulindac activation; however, sulindac-induced gastrointestinal injury, which is caused by irritation of the gastrointestinal tract by its active metabolite, is uncommon. Therefore, it is surmised that sulindac is converted to its active metabolite in tissues after absorption. In this study, we sought to identify the enzyme(s) responsible for sulindac activation in tissues and to compare its/their contribution to the gut microbiota. Sulindac is enzymatically reduced in human intestinal, liver, and renal cytosols. Since sulindac is known to be reduced by methionine sulfoxide reductase (Msr) in Escherichia coli, we investigated whether the human ortholog MSRA catalyzes the sulindac reduction reaction. We found that recombinant human MSRA shows sulindac reductase activity with a similar Michaelis constant value as tissue cytosols. In addition, it was revealed that cytosolic factor(s) efficiently enhanced MSRA activity. By using the relative expression factor, the contribution of MSRA to the sulindac reductase activities in each tissue cytosol was calculated to be almost 100%. In mice, depletion of the gut microbiota by administration of antibiotics resulted in a 31% decrease in the area under the curve ratio of sulindac sulfide to sulindac, indicating that the contribution of tissue MsrA to sulindac activation is expected to be 69% in the body. In conclusion, we demonstrated that MSRA expressed in tissues is involved in sulindac activation, making a larger contribution than the gut microbiota. SIGNIFICANCE STATEMENT: Methionine sulfoxide reductase A is responsible for the activation of sulindac, a nonsteroidal anti-inflammatory prodrug, to sulindac sulfide, an active form, in human tissues. Methionine sulfoxide reductase A expressed in tissues activates sulindac with a higher contribution than gut microbiota in body.

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(1)169 that	(11)5 good	(21)3 that,	(31)2 leadership
(2)48 a	(12)5 using	(22)2 altered	(32)2 on
(3)34 the	(13)5 with	(23)2 benefits	(33)2 positive
(4)18 in	(14)4 comparable	(24)2 decreases	(34)2 potential
(5)17 to	(15)4 for	(25)2 elevated	(35)2 robustness
(6)16 by	(16)4 how	(26)2 evidence	(36)2 significantly
(7)9 an	(17)4 its	(27)2 greater	(37)2 similar
(8)8 significant	(18)3 improved	(28)2 higher	(38)2 statistically
(9)7 null	(19)3 no	(29)2 highly	(39)2 successful
(10)7 efficacy	(20)3 several	(30)2 increased	(40)2 survival

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--- WordNet output for demonstrated --- Overview of verb demonstrate The verb demonstrate has 4 senses (first 4 from tagged texts) 1. (24) show, demo, exhibit, present, demonstrate -- (give an exhibition of to an interested audience; "She shows her dogs frequently"; "We will demo the new software in Washington") 2. (22) prove, demonstrate, establish, show, shew -- (establish the validity of something, as by an example, explanation or experiment; "The experiment demonstrated the instability of the compound"; "The mathematician showed the validity of the conjecture") 3. (2) attest, certify, manifest, demonstrate, evidence -- (provide evidence for; stand as proof of; show by one's behavior, attitude, or external attributes; "His high fever attested to his illness"; "The buildings in Rome manifest a high level of architectural sophistication"; "This decision demonstrates his sense of fairness") 4. (1) demonstrate, march -- (march in protest; take part in a demonstration; "Thousands demonstrated against globalization during the meeting of the most powerful economic nations in Seattle") Overview of adj demonstrated The adj demonstrated has 1 sense (first 1 from tagged texts) 1. (1) demonstrated -- (having been demonstrated or verified beyond doubt) --- WordNet end ---