Talk:P-glycoprotein

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Above undated message substituted from

"Increased intestinal expression of P-glycoprotein can reduce the absorption of drugs that are substrates for P-glycoprotein. Thus, there is a reduced bioavailability, therapeutic plasma concentrations are not attained. On the other hand, supratherapeutic plasma concentrations and drug toxicity may result because of decreased P-glycoprotein expression Active cellular transport of antineoplastics resulting in multidrug resistance to these drugs"

I'm unclear on this, but if the P-gp is pumping the substance out of the cell, then wouldn't PLASMA concentrations GO UP (not down) ? Eg. would the problem be that there's PLENTY (or too much) medication in the Plasma, and TOO LITTLE in the Target Tissue (eg. inside the cells) ? — Preceding unsigned comment added by 129.78.64.100 (talk • contribs) 06:47, 20 February 2007 (UTC)[reply]

There should be relevant material here on the polymorphisms that can inhibit Pgp and cause increases in serum concentration of drugs (i.e digoxin). Not common, but common enough that people should be able to read about it. — Preceding unsigned comment added by 141.106.138.43 (talk • contribs) 18:07, 6 May 2007 (UTC)[reply]

Response to the above:

No - PGP is expressed on the luminal surface of the intestinal cells (enterocytes). This is the surface that makes contact with the lumen (hollow tube) of the intestine. Drugs try and get into the bloodstream via the enterocytes. However, they have to get past the luminal surface of the enterocytes to do this (tight junctions between the cells prevent drugs squeezing between enterocytes). PGP stops drugs getting into the enterocytes - as soon as they get in, it pumps them back out, into the lumen of the intestine. This means that instead of getting to the plasma, drugs are excreted via the intestine. — Preceding unsigned comment added by 81.104.186.166 (talk • contribs) 17:53, 30 October 2007 (UTC)[reply]

Was the protein cloned in 1976, as written? Seems unlikely. (I don't have access to the article, so I can't check.) — Preceding unsigned comment added by 78.149.99.186 (talk) 02:47, 17 May 2014 (UTC)[reply]

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Essentially all sources used in this article are primary sources. The reliance on secondary literature is not mandatory by

WP:MEDRS

. I quote:

For biomedical content, primary sources should generally not be used. This is because primary biomedical literature is exploratory and often not reliable, and any given primary source may be contradicted by another. The Wikipedia community relies on guidance of expert reviews, and statements by major medical and scientific bodies. Text that relies on primary sources should usually have minimal WP:WEIGHT, only be used to describe conclusions made by the source, and must describe these findings clearly so that checking can be made by editors without specialist knowledge. Primary sources should never be cited in support of a conclusion that is not clearly made by the authors (see WP:Synthesis).

This is a low level article and avoiding primary sources would essentially mean deleting the entire article. It is therefore unclear why Jytdog object to this particular edit, and not to any other content in this article. In the case of this particular article cited in support, it has more than 300 citations (Scholar) and was published in a generally well-regarded outlet (The Lancet). Thus, I can see no particular reason to avoid it given the discussion in

WP:MEDRS. Ethnic differences in alleles are very common, particularly for African vs. non-Africans, so this finding is not likely to fail replication. From my skimming of the later literature, it seems that variants in this gene have been confirmed to be related to the immune system by later studies. Furthermore, this edit is rather counter-productive. Why delete an entire section instead of just finding a secondary source yourself and adding it? In my case, I actually found this study while reading a reliable secondary source, WHO's Genomics and world health : report of the Advisory Committee on Health Research (2002). Would Jytdog object to this section if this secondary source was also used? Of the >300 citations, many of them are suitable secondary sources, so if a newer source is sought, one could easily be found. For instance, Wolking et al (2015) writes in their literature review

that:

All common coding sequencing variants with a minor allele frequency of [ 0.01 in at least one ethnic population are listed in Table 2 . The three most studied variants are 1236C [ T , 2677G [ T/A and 3435C [ T . 3435C [ T is located on exon 26 and translates to isoleucine located in the second ATP-binding domain (Fig. 2 ). This SNP shows remarkable inter-ethnic variability [ 54 ]. The 3435T allele has prevalence rates of 0.17–0.27 in Africans, 0.41–0.66 in Asians and 0.48–0.57 in Caucasians [ 55 – 59 ]. 1236C [ T translates to glycine. The frequency of the C allele ranges between 0.29 and 0.93, depending on the population, C being the minor allele in Asian populations and T being the minor allele in African populations. The tri-allelic variant 2677G [ T/A causes substitution of alanine by serine or threonine located in the intracellular region of the trans- porter. According to dbSNP, the frequency of the reference allele ranges between 0.38 and 0.85, depending on eth- nicity. The T allele is more common in Asian populations than in African populations. The A allele is very rare, with a prevalence of 0–0.17, depending on ethnicity [ 56 , 60 ]. The three most common variants, 1236C [ T , 2677G [ T/ A and 3435C [ T, show strong linkage disequilibrium, and the haplotypes CGC and TTT have been characterized in most ethnic groups [ 61 – 64 ]. The frequency of the haplo- types is subject to inter-ethnic variability. For instance, the TTT haplotype occurs significantly less often in African populations than in Caucasians and is the most common haplotype in Asians [ 54 , 57 , 63 ]. Regarding the functional role of the closely linked variants 1236C [ T , 2677G [ T/A and 3435C [ T , any impact of the two synonymous SNPs could derive from the linkage disequilibrium with the missense variant 2677G [ T/A . Alternatively, it has been suggested that 3435C [ T could act by reducing messenger RNA (mRNA) stability [ 65 ] or by affecting the timing of folding and membrane insertion of the protein, resulting in a change in substrate specificity [ 6 , 66 ].

I.e. the ethnic variation has been well-replicated and does not seem controversial. Does Jytdog still want to delete the section given that many secondary sources exist (two cited above), and if so, why. Deleet (talk) 21:59, 18 August 2017 (UTC)[reply]

Please use secondary sources for content about health. Thanks. Jytdog (talk) 22:27, 18 August 2017 (UTC)[reply]

• Thanks for providing a recent review in this diff. I summarized what that review said, here. this is why we use reviews. Jytdog (talk) 03:05, 25 August 2017 (UTC)[reply]

However, there was no reference spamming. The two edits added a total of 2 new citations to the article. Having multiple citations for claims is common practice. I have no idea why Jytdog invokes REFSPAM. The edits were not made by me. --Deleet (talk) 01:33, 25 August 2017 (UTC)[reply]

had already explained to you here on your talk page, when you posted this. Jytdog (talk) 03:04, 25 August 2017 (UTC)[reply]

Content Materials are organized based on the headings, in each heading the content focuses on the topic tightly, but just slightly lacks reasonable orders. Basically, the presentation is understandable, but if some examples could be provided to back up some terms and professional claims, the article could be better presented. The article covers the topic in a lot of aspects, from my view, after reading through all the article I gained a nearly complete understanding of P-gp, compared with what I already learnt about the P-gp. Though I need to pay attention to each detail, I can find almost all what I know in the article, except for professionalized knowledge such as involved signaling pathways.

Quality The article has an introduction and the introduction of the article is well organized. The introduction contains several, but not too many terms, while the terms included are not too specific, which makes the introduction not too hard to understand. The flow of the introduction follows the list of headings well, by briefly covering nearly all the aspects in the content (except for ‘History’ and ‘Research’). The introduction summarizes the major information of all aspects, which makes it a quick and informative introduction. There are about 10 headings and subheadings, the contents of headings and subheadings are much more detailed and specific than the corresponding contents in the introduction. For example, for ‘protein’, in the introduction, the article only mentions P-gp as a member of ABC transporter superfamily, but in the content, transmembrane domains (TMDs) that binds substrates, and highly conserved ATP-binding sites (NBDs) are introduced. In the content, the detailed structure of P-gp is introduced using primary classical articles as evidences, which are well cited.

Three images and three tables are on the right side of the article, and appendices and footnotes are at the end, which note the reference of the pictures and tables. Links are also presented. Once click on the links, the readers will be guided to separated page showing the original resource of the pictures/tables. Some of the pages include the tools used to generate the pictures/tables.

Both the general functions and the implication of P-gp in diseases are introduced in a balance. From my own point, the role of P-gp in cancer drug resistance is introduced dispersedly but not stressed in this article, which should be considered as a sign of neutral coverage. However, because even in the ‘Clinical significance, Diseases’ part I did not see the implication of P-gp in cancers, therefore I feel more stress on cancer should be added into the article.

Evaluation on evidences In the article, facts are emphasized: the whole article uses passive voice consistently and thus presents related facts coherently. I did not see any subjective assumptions or opinions. Basically, all evidences (references) are review articles in cell biology and disease research. Though I think more primary articles, instead of the review containing the primary articles, should be added in to specifically support claims, I feel the quality is fine, because the evidences are up to date: though some evidences are from 1900’s, also four new evidences after 2015 were found. Moreover, the introduced methods by the reference used to measure P-gp activity are still being used currently. One place I think needs to be improved is when the article talking the function of P-gp, it states that ATP hydrolysis is the step causing the conformational change of P-gp, however the order of ATP binding, conformational change, and ATP hydrolysis are still under debating, and some believes the binding of ATP, rather than the hydrolysis of ATP, causes the conformational change. Because no references are listed here, I have no idea based on which reference the conclusion of P-gp function is drawn. I would improve this part by providing up-to-date mechanisms of functions, and might provide multiple mechanisms with clearly cited references. The reliability of evidences is good, because the evidences either come from literatures (with PMIDs) or from qualified databases, such as Ensemble, or Gene of pubmed. The only exception is one evidence is from FDA website, which is also considered as a reliable recourse.

Missing contents and how it would be improved From my view of point, the introduction seems informative but highly summarized, missing of even brief examples would make it too condensed to new learners of P-gp. For example, when the article mentions that some cancer cells express P-gp, it does not provide any example of cancer cells; I think if types of cancers could be provided here as examples, the significance of P-gp in cancer drug resistance would be given in a more straightforward way. Another example is when the article states that current P-gp inhibitors work incidentally but not as their main mechanism of action, if a few (1-2) examples, such as verapamil, could be given, the audience would also get a better understanding of this sentence, also professional audiences such as researchers searching for specific inhibitors for P-gp could quickly find useful information here.

In the ‘Clinical significance, Drug interactions’ part, a variety of P-gp inhibitors are provided, however, for general audience, it seems very hard for them to really know about the inhibitors merely by looking at the names. If the inhibitors could be sorted by the mechanism of actions, or the other ways, the audience could have a much clearer idea about the inhibitors.

In the ‘Clinical significance, Drug interactions’ part, a variety of P-gp inhibitors are provided, however, for general audience, it seems very hard for them to really know about the inhibitors merely by looking at the names. If the inhibitors could be sorted by the mechanism of actions, or the other ways, the audience could have a much clearer idea about the inhibitors.

As mentioned above, because the role of P-gp in cancer drug resistance is not listed even in the ‘Clinical significance, Diseases’ part, therefore I would improve this part by adding the implication of P-gp in resistance to cancer chemotherapeutics.

As a cell biology and cancer researcher, I tried to find the expressional regulation of P-gp but I did not. I think if this piece of information could be added, it could be useful to people doing researches, for example, once know the map of regulatory mechanism of P-gp, researchers can then pick members involved in P-gp regulation as targets. The information of expressional regulation of P-gp does not need to be very detailed with examples, but would better cover a variety of regulatory pathways and achieve in drawing a whole picture. I am planning working on adding a paragraph of regulatory mechanisms of P-gp in human cancer cells.

Woshiau (talk) 13:13, 26 October 2017 (UTC)[reply]