Chemistry and Life

Medicinal chemistry. Pharmacology. Toxicology. Environmental sciences.

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Bisphenol S is replacing bisphenol A (BPA), but is it any safer?

Bisphenol A (BPA), a chemical used in some types of plastics, has gotten a lot of public attention in recent years because of its estrogen mimicking effects and the public’s widespread exposure to it. Many manufacturers have removed BPA from products which come into contact with food, and in some jurisdictions there are now regulations limiting its use.

One of the chemicals that is used as a replacement for BPA is bisphenol S (BPS). BPS is chemically related to BPA and actually has the same inherent estrogenic activity which is problematic in BPA. However, BPS was thought to be a safer alternative because, it was claimed, it did not leach from plastics like BPA does.

That belief is now being questioned. An article at Scientific American details some of the research and concludes that the real issue behind the public safety problem is not so much that we can’t determine the health concerns associated with a particular chemical but that, “Currently, no federal agency tests the toxicity of new materials before they are allowed on the market.”

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Mayapple and podophyllotoxin

May apple leafThe woods here in Pennsylvania at this time of year are starting to burst into their summer greenery. One of the plants that is prominent at the moment is the mayapple (Podophyllum peltatum). It is a small herbaceous perennial with an umbrella-like leaf on a single stalk. Underneath this umbrella a single flower blooms which eventually grows into a fruit, the “apple”. The fruit is edible when ripe, but the roots and leaves are quite poisonous.  Even touching the root may cause dermatitis.

The extract of the root (actually a rhizome) is known as podophyllin.  This extract is a complex mixture of chemical compounds including flavonols and lignans.  One of those lignins, podophyllotoxin, is the individual toxin primarily responsible for the poisonous nature of the plant.

Mayapple flowerAs is sometimes the case with poisonous plants, the mayapple has found use medicinally.  Native Americans and early American settlers used it for a variety of ailments.  In modern medicine, both the mixture podophyllin and the purified compound podophyllotoxin have found use in the topical treatment of warts.

Medicinal chemists have also taken note of the properties of podophyllotoxin.  Two semi-synthetic derivatives of podophyllotoxin, teniposide and etoposide, have been developed as pharmaceutical drugs for use in cancer treatment.  These two drugs act as topoisomerase inhibitors.

So it seems we’ve progressed from using the whole plant to using a crude extract, then to using a purified chemical, and finally to using semi-synthetic derivatives designed to hit a specific target enzyme.  What comes next?


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Is bisguaiacol F a viable alternative to bisphenol A?

Bisphenol A (BPA) is an ingredient in some plastic products.  It is useful in improving the properties of materials and products it is used in, but it has become a controversial subject.  BPA is used in plastic water bottles, food containers, and other materials that come in contact with what we consume.  BPA is used in small amounts and our exposure to it is probably very small. But BPA has known acute adverse health effects as an endocrine disruptor, and the human health risks associated with long term low exposure levels are difficult to assess. Figuring out how to balance the competing interests of a useful product versus the health concerns associated with its use is a messy regulatory situation.

As a precaution, BPA is has been phased out from some uses and has been banned in some jurisdictions and the search for suitable replacements is an area of active research.  One potential replacement that has been reported recently is called bisguaiacol F (BGF).  One notable aspect of BGF is that is can be produced from waste byproducts of the paper industry.  Lignans are natural chemical compounds found in wood which are removed in the production of paper.  This lignin waste is a disposal problem, so if it can be converted into a useful product (which is a replacement for a potentially harmful product) then two birds are killed with one stone.

Chemical structures of bisguaiacol F (BGF, top) and bisphenol A (BPA, bottom)

Chemical structures of bisguaiacol F (BGF, top) and bisphenol A (BPA, bottom)

So, is BGF a viable alternative to BPA?  BGF is chemically related to BPA.  Comparing the two chemical structures shown in the image, the two methyl groups (CH3) in the middle of BPA are removed and two methoxy groups (CH3O) are added on the ends.  Looking at just the first modification, removal of the two methyl groups gives a compound called bisphenol F (BPF).  BPF is a has the same endocrine disrupting concerns as BPA, so this modification alone is not sufficient to eliminate the potentially harmful effects.  Looking at the second medication, the study’s authors claim that the introduction of the two methoxy groups will prevent BPF from binding to the estrogen receptor, which is the cause of BPA’s biological effects. As far as I can tell, the researchers have only used software models to predict the biological effects of BGF, so there is certainly quite a bit more work to be done to demonstrate its safety.

It is still too early to tell whether BGF will eventually be a viable replacement for BPA, but it is research like this that is the only real hope of bypassing the current messy regulatory situation.


Soursop and annonacin

Soursop is a tropical fruit from the plant Annona muricata.  It is also sometimes called graviola or pawpaw.  It is apparently becoming popular as a dietary supplement.  Extracts have been shown to be able to kill some types of cancer cells in vitro (in “test tube studies”).  There doesn’t appear to be any clinical study in humans, but that hasn’t stopped supplement manufacturers from claiming soursop to be an all-natural miracle cancer cure.

The bioactive constituents of soursop have been identified as members of the acetogenin class of compounds.  In particular, soursop contains a chemical called annonacin that has been found to posses in vitro anticancer activity; for example, it can cause cell growth arrest and apoptosis in the MCF-7 breast cancer cell line.

However, annonacin is also a neurotoxin.

This is a common problem encountered by medicinal chemists.  When optimizing chemical compounds for one particular desirable pharmacological effect, one can also get an unwanted “off-target” effect that is associated with it. These off-target activities can be the source of a pharmaceutical drug’s side effects. It is often hard to get rid of these off-target activities entirely, so the idea is to find compounds that maximize the ratio between desirable and undesirable effects.

For annonacin, investigators are looking into the fact that it is a mitochondrial complex I inhibitor, which can lead to destruction of neurons and gives rise to the potential to cause neurodegenerative disease. There are also a number of published studies that show an association between heavy consumption of soupsop and Parkinson’s disease, or more broadly, atypical parkinsonism.

The research that makes a connection between soursop and anticancer effects is preliminary and hasn’t been established in humans.  The research that makes a connection between soursop and neurodegeneration spans in vitro studies, animal studies, and epidemiological studies.  For a health supplement, that certainly doesn’t sound like a good bet to me.

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AzodicarbonamideAzodicarbonamide is used as a food additive in bread making.  In the United States and Canada, its use is permitted in low levels (45 ppm).  In Europe, it is not permitted.  Azodicarbonamide is also used industrially as a “blowing agent” – upon heating, it releases nitrogen and other gas bubbles that allow production of foamy materials.

Recently, azodicarbonamide has gotten quite a bit of attention in the news.  U.S. Sen. Charles Schumer recently asked the Food and Drug Administration to ban it.  And Subway Restaurants announced earlier this week that they will stop using it in their bread.

The safety of everything added to food is naturally a valid concern, but what really bothers me about the news reporting of azodicarbonamide is the repeated comments that it is also “used to make yoga mats and shoe rubber”.  (Some examples here and here.)  Whether or not azodicarbonamide is safe to use in the food we eat is, of course, in no way dependent on what else it may be used for.  That’s like complaining that we shouldn’t use yeast in bread because it produces the same chemical, carbon dioxide, that is also used as a blowing agent in making foamed plastics.  This nonsense about yoga mats and shoe rubber is an illogical and unscientific appeal to emotion, used solely for sensationalist and inflammatory reasons, as if maybe eating bread with this food additive in it is like eating bread with shoe rubber in it.

Please, just stick with the science.  What amount of azodicarbonamide remains in the bread after cooking?  What are the potential health effects of consuming bread with that amount of azodicarbonamide?  What impact does that have on the appropriateness of current regulations?

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EDC Properties of Cadmium

This post on the Toxcentre blog is a nice review of the endocrine disrupting properties of cadmium.


Author –

The topic I have chosen to explore is how the metal cadmium (Cd) may potentially result in endocrine disruption. Endocrine disrupting compound (EDC) are those that have the potential to alter hormone pathways that regulate reproduction (Arcand-Hoy and Benson 1998). They have investigated widely in the literature as have the release of metals through anthropogenic activities.  Cadmium is a naturally occurring metal but it is not essential in normal cellular processes so exposure and uptake of Cd can have adverse effects. Cadmium exposure can occur through ingestion of food or water containing Cd as well as inhalation. Inhalation exposure occurs most notably through cigarette smoke but also from coal burning. Cadmium can be food in food that is grown in soils containing either naturally higher Cd levels or in areas where the soil has been increased through anthropogenic uses (Silva et al. 2011).

Cadmium has been identified as…

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