Picture it…

Chemistry

Grapefruit (Citrus paradisi)

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You may be used to having a glass of grapefruit juice with your breakfast, or may have even eaten a grapefruit today (probably with a lot of sugar on it, though). Our main image shows a cut grapefruit resting on a lab bench, next to the structure of the molecule (R)-thioterpiniol.

Figure 1: A grapefruit (left), next to a pomelo.

1) The grapefruit is a naturally arising hybrid of the orange and the pomelo, both of which were originally from South Asia, but which were grown together in Barbados (Morton, J. 1987. Grapefruit. p. 152–158. In: Fruits of warm climates. Julia F. Morton, Miami, FL.). It’s thought to be called a grapefruit because it grows in clusters like grapes, though it is possible that it was originally called the greatfruit, after the Latin name for the pomelo, citrus maxima.

The first thing you may notice about the grapefruit is its bitter taste, which is due to the molecule naringin (figure 2); grapefruit is usually eaten with plenty of sugar to mask the bitterness. However, in America during and after the first and second world wars, an advertising campaign tried to persuade people to eat grapefruit with salt. This was because sugar was rationed, so the government put out a campaign to encourage citizens to use table salt as an alternative. Bizarrely, there is scientific evidence to suggest that this could actually help with the bitter taste, as the ions in salt block the receptors on your tongue which are responsible for the bitterness.

Figure 2: Naringin, the molecule responsible for grapefruit’s bitterness.

2) One of the problems with eating grapefruit is the so-called ‘grapefruit juice effect’, the propensity of grapefruit juice to interfere with prescription medicine (and illegal drugs!) (Expert Opin. Drug Met., 2011, 7, 267–286). This was accidentally noticed in 1989, during a trial to investigate whether alcohol had an effect on a drug called felodipine; grapefruit juice was used to mask the taste of the alcohol, but it was found that it also markedly increased the amount of felodipine in the blood. (Am. J. Med., 2016, 129, 26 – 29).

Since then it has been established that the effect is due to chemicals in the grapefruit juice inhibiting an enzyme in the body called cytochrome P450 3A4 (CYP3A4). This is responsible for metabolising many substances that enter the body, including drugs, by oxidising them. So, although 100% of felodipine is absorbed through the intestine, on average only 15% enters the bloodstream; the rest is metabolised by CYP3A4 as it passes through the gut wall and liver, an effect known as First Pass Metabolism. However, drinking grapefruit juice can triple the amount that enters the bloodstream, and one glass prior to taking medication is enough to have a pronounced effect (Br. J. Clin. Pharmaco., 1998, 46, 101–110). For some drugs, the grapefruit juice effect can cause more than a 7-fold increase in the amount in the blood, and the effect is long lasting because the inhibition is irreversible; it persists until the body has made new enzyme.

The chemicals responsible are called bergamottin, 6′-7′-dihydroxybergamottin, and the exotically named paradisin C, which belong to a class of compound called furanocoumarins (Figure 3). Their role was established by removing them from grapefruit juice and noticing that the effect disappeared (Am. J. Clin. Nutr., 2006, 83, 1097-1105), and indeed there are now efforts to breed grapefruit that do not contain these chemicals (Nat. Biotechnol., 2013, 31, 186). Conversely, there are also studies that try and use the effect of bergamottin in a positive way, by using it to deliberately increase the amount of drug that gets into the bloodstream (Int. J. Mol. Sci., 2018, 19, 4048).

Figure 3: The chemicals which cause the ‘grapefruit juice effect’.

It is now known that a wide range of drugs are affected by the grapefruit juice effect, enough for the US Food & Drug Administration to issue an official warning. Generally, it is found that too much drug enters the bloodstream, because the CYP3A4 enzyme that normally gets rid of it is inhibited; but for some drugs, too little enters the bloodstream. Investigating this latter effect established that the grapefruit juice was having a second role and preventing the drugs from getting into cells by inhibiting molecules called organic anion transporter proteins, which play a part in helping drugs across the cell membrane (Clin. Pharmacol. Ther., 2012, 92, 622-630). This inhibition is reversible and only lasts for a few hours, so not drinking grapefruit juice before taking the drug is sufficient to avoid this problem (Brit. Med. J., 2013, 346). In this case it is the naringin (Figure 2) that is having the effect (Brit. J. Clin. Pharmacol., 2010, 70, 645–655).

Figure 4: A grapefruit, drawn in 1912.

3) Besides its characteristic taste, grapefruit also has a distinctive smell. This is mainly due to the grapefruit mercaptan (properly known as (R)-thioterpineol) (Figure 5), which is found in the fruit at parts per billion level, but which is potent enough to create the distinctive smell. (Helv. Chim. Acta, 1982, 65, 1785-1794). Chemists might recognise the similarity of this to limonene; it belongs to the same class of molecule, called terpenes, and can be synthesised in the laboratory from it. 10 mg of this will set you back about $175, but it’s so smelly that you don’t need much.

A second characteristic grapefruity molecule is called nootkatone; as well as grapefruit peel it can also be found in a species of tree called Cupressus nootkatensis, hence the name. Not only is this molecule used to impart grapefruit flavours and smells to food, but it also turns out to be a highly effective insecticide, now available as Mozzi Magic. However, much like the mercaptan above it’s only present in tiny amounts in grapefruit, and making 1 kg of nootkatone require 400 tons of grapefruits, which is why it can cost up to £4000 per kg. Given its use as a food additive and its potential as an insecticide there’s therefore a clear commercial imperative to develop a cheaper synthesis.

The precursor molecule to nootkatone is called valencene, which can be extracted from oranges or fermented by yeast from sugar. The traditional method of converting valencene to nootkatone is by oxidation using a fairly strong chemical oxidising agent, but a team from Oxford have recently started doing it by using the principles of synthetic biology. One variety of the same CYP450 enzyme discussed above oxidises camphor but would not oxidise valencene, which is a bigger molecule and which is known to inhibit CYP450, but by selectively modifying the enzyme to make the binding pocket bigger and more hydrophobic it was found that it could be made to work (Org. Biomol. Chem., 2005, 3, 57-64). The Oxford group have now commercialised this process.

Figure 5: Nootkatone and thioterpineol are some of the molecules that give grapefruit its taste and smell.

So, it turns out that grapefruit and the chemicals in it can have both positive and negative benefits. It still tastes horrible though.

Contributors: Emily Wilson (writing), Chris Adams (writing and editing), Natalie Fey (pictures)

Image credits: Figure 1 from user Gaurav, from Wikimedia Commons under the under the Creative Commons Attribution 4.0 International license. Figure 5 from National Agricultural Library, Agricultural Research Service, U.S. Department of Agriculture, via Wikimedia Commons. All other figures home-made.

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