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About Retinoic acid

Half a century later, the story of the failure of retinoic acid WIN 18,446, described earlier, helped to move in the direction of male contraception. Since WIN 18,446 poisoned only those who took alcohol, scientists suspected that, most likely, this drug violates some of the stages of the natural breakdown of ethanol in the body.

Ethanol contained in wine, beer and other alcoholic beverages, entering the body, is metabolized to acetaldehyde. Acetaldehyde is very toxic, and an enzyme called ALDH (acetaldehyde dehydrogenase) neutralizes it, turning it into acetic acid.

In 2010, it was found out that WIN 18,446 binds to ALDH and stops the whole process, which leads to the accumulation of acetaldehyde and, accordingly, poisoning. This discovery turned out to be quite useful. In the testes, there is also a process of converting alcohol into acid, only not ethanol, but retinol (one of the forms of vitamin A) into retinoic acid. During spermatogenesis, retinoic acid binds to the RAR protein, forming a complex necessary for the maturation of spermatozoa from progenitor cells. In the testes, a special aldehyde dehydrogenase ALDH1a2 is engaged in the conversion of retinol into retinoic acid. This means that if you correct the binding features of WIN 18,446, you can make it ignore ALDH, and block only ALDH1a2 in the testes, which would prevent poisoning.

It was not possible to do it with a rush. About a hundred variations of WIN 18,446 were tested, and none worked. Cheerful scientists scanned another 60,000 molecules and still found seven (!) that specifically blocked ALDH1a2. But this is not the end — some of these molecules may be toxic or will not be able to overcome the hemato-testicular barrier. So, clinical trials are still very far away.

The story of WIN 18,446 prompted several more laboratories to pay attention to the role of retinoic acid in spermatogenesis. One of these laboratories at Columbia University in New York, using screening, discovered a substance that blocks the binding of retinoic acid to the RAR protein. At the same time, the genes necessary for sperm maturation are not activated at all. But even in this case, it was not without difficulties. The effect of such a drug turned out to be systemic — retinoic acid could not bind to proteins similar to RAR in other tissues. And now the creators of the drug are struggling to make it testis-specific.

The head of this group of scientists, Debra Wolgemuth, like many of her colleagues in this field, considers her work important not only for family planning, but also for maintaining an adequate level of the total population of the Earth (according to some forecasts, the world’s population may grow to 10 billion by the middle of this century). Testing of contraceptive drugs on laboratory rodents also gave Debra a very useful idea about how to rid the New York subway of rats. Well, this is a topic for a separate article.

Sensational breakthrough

In addition to the participants of the retinoic acid cascade, there are hundreds of genes expressed only in the testes. And “turning off” any of them can stop the “pipeline” of spermatogenesis.

One of the most elegant attempts of such “sabotage” was recently successfully undertaken by scientists from Boston and Houston. In the process of screening potential anti-cancer drugs a few years ago, scientists discovered a substance called JQ1 (thienosepin inhibitor, Fig. 2b), which inhibits the division of cancer cells. This happens due to the binding of JQ1 with special proteins that have a bromodomain.

One of the goals of the study was to analyze how JQ1 will behave in different tissues. And it turned out that in mice, this drug is able to inhibit the testis-a specific bromodomain-containing the BRDT protein. This protein is very conserved functionally and structurally, which means that human BRDT can also be inhibited by JQ1. This BRDT is engaged in the fact that it specifically modifies histones-proteins on which DNA is wound.

In BRDT, two bromodomains that recognize hyperacetylated lysine in histone H4 (Figure 2a), thereby contribute to the activation of many genes necessary for spermatogenesis (Figure 2b). JQ1 is just a structural analog of acetylated lysine. It can interact competitively with BRDT, preventing the latter from contacting histone. Previously, it was known that mice with a deletion of the BRDT bromodomain or with a knockout for this gene are sterile, and many clinical cases of fertility disorders in men are associated with mutations in this gene. Everything pointed to the fact that JQ1 has great potential as a male contraceptive.

about retinoic acid

After testing on mice, it became clear that this was a success: with BRDT blocked, spermatogenesis stopped in the middle, but even those sperms that managed to get into the lumen of the seminal tubule could almost not move (mobility was reduced by 4.5 times). When male mice were regularly given JQ1 for 3-6 weeks, the size of their testes decreased to 40% of the norm, and this was accompanied by a significant decrease in the number of spermatozoa (up to 11% of the norm). It is very important to note that the level of sex hormones has not changed. This means that it will be possible to avoid side effects that were associated with hormonal disorders during previous attempts to create male contraceptives!

How is spermatogenesis magically blocked by the action of a JQ1 inhibitor? Due to its small size, the JQ1 molecule is able to overcome the hemato-testicular barrier and enter the sperm progenitor cells, where it immediately binds to the BRDT protein. Analysis of the structure of the BR DT/Q1 complex showed that the active center of the BRDT bromodomain is completely occupied by a small molecule JQ1. As a short digression, it is worth noting that chromatin-associated proteins, such as BRDT, are usually involved in the processes of regulating gene expression. The authors of the work used microchips to study the expression of genes in the testes with a blocked BRDT bromodomain, and it turned out that hundreds of genes, including many that are absolutely necessary for spermatogenesis, practically stop working.

But still, the most remarkable property of JQ1 was the reversibility of its contraceptive effect. To the relief of many who have read the article to this point, I inform you that the authors have convincingly shown that the size of the testes and the number of spermatozoa have recovered to 100% of the norm, and the experimental male mice were able to become fathers of healthy mice already four months after stopping taking JQ1.

Retinoic acid – conclusions

Of course, the creators of the drug will have to work a lot more on the specificity of the effect of JQ1 on the testis-specific BRDT. But maybe this is just the case when scientists will still be able to outwit nature and create an effective, safe, cheap, easy to manufacture, easily portable without side effects, and most importantly, having a reversible effect, a male contraceptive pill!

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