The Antiepileptic, Valproic Acid – A Mutagen?
As a medicine, valproic acid (VPA) has a variety of uses. Not only does it serve as an antiepileptic drug, it can also be used for mood stabilization in Bipolar, and has even found more recent use as an anti-cancer agent for certain types of tumors . While it has already been well-established as a teratogen (a promoter of certain birth defects) there is a small body of literature that suggests VPA may also promote DNA mutations in those people taking the drug and in the offspring of mothers taking it during pregnancy [2 & 3, for examples].
The primary finding in these studies has been one of increased sister chromatid exchange (SCE). As is probably implied by the name, SCE is the exchange of genetic material between sister chromatids. (Wow, did that sound as redundant as I think it did? Anyways, see the image below.) This often occurs when a single chromatid is damaged and the missing material is then duplicated and supplied by the other chromatid. This can lead to mutation through repair because the homologous allele frequently doesn’t contain the same sequence as in that of the damaged segment. Just picture your cells having to use the genetic material your mother gave you to repair damage to your father’s genes.
Double-stranded breaks are often a cause of SCE:
Valproic acid has a variety of downstream effects in tissues, but two of its direct effects are 1) blocking the synthesis of the carbohydrate, myo-inositol, a molecule integral to a number of second messenger systems within the cell, and 2) as a histone deacetylase (HDAC) inhibitor. For the purposes of mutegenicity this latter effect may be most important. HDACs function, as their name might imply, by deacetylating histones. Histones are proteins that aid in packing DNA into nucleosomes, a regulatory mechanism of gene transcription. As you can see from the image below a number of different histone proteins make up the larger octamer unit around which the DNA is wound.
When a histone complex is acetylated, meaning that negatively-charged acetyl groups have been added to it, it loses some of its overall positive charge which decreases its capacity to interact with and bind tightly to DNA. This leaves the local DNA available for transcription (gene expression). Therefore, HDACs actively remove acetyl groups, allowing histones to better bind to DNA and maintain it in a closed form. Below you can see the chemical formula for an acetyl group which is comprised of a carbonyl group (a carbon double-bonded to an oxygen) and a methyl group; “X” is whatever the acetyl group happens to be bound to, in this case an amino acid, lysine, within the histone protein.
Why might VPA’s capacity to inhibit HDACs be so important when it comes to genome stability? I mean, hell, so the DNA’s a little unwound, maybe it’s a little more available for transcription. How could that make it less stable?
Well, there’s growing evidence to suggest that histone deacetylation is vital for not only maintaining genomic stability but also in repair processes [4, 5]. On average, the less “packaged” the DNA is, the more vulnerable it is to instability for a variety of reasons.
And so if we take this information and apply it to what we know about increased occurrences of sister chromatid exchange in cases of VPA exposure, it begins to make sense how a drug that inhibits HDAC activity could promote increased rates of certain types of mutations. We can expect those cells exposed to an HDAC inhibitor like valproic acid to be hyper-acetylated, in which the DNA is not tightly wound around the histone octamers and therefore genome stability is at higher risk.
Valproic acid has been an incredibly useful drug. For some epileptics and people with Bipolar it improves quality of life and makes their conditions more manageable; and for some people with cancer it’s no doubt even been a life saver. But I guess the takehome message of this story, aside from reminding the reader how truly delicate and mutable the genome is, is how delicate life itself can be. So be careful what you put in your body, because it’s the only one you’ve got.
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