Sucralose: The Misunderstood Ubiquitous Sweetener – Part 1



By: Ben Esgro, B.S., CSCS, CISSN


Sucralose (Splenda®) is an artificial sweetener that is present in nearly all reduced calorie or calorie free foods.  Although much research has been performed on this compound, it remains largely debated and misunderstood by the common consumer.  Before delving into the research and chemistry of Sucralose, a brief discussion on natural (created in nature) vs. man-made compounds would appear appropriate and relevant.

               The most common argument against the use of Splenda and other artificial sweeteners is that they are not “natural”; therefore this makes them inherently unsafe.  Also, due to the incredible accessibility of the internet, anyone can type the term “sucralose” into a search engine and come up with an endless list of opinion based web pages that bash the sweetener on unfounded claims.  It is far from circumstantial that these pages rarely if ever are accompanied by citations or references to actual literature.  Websites like these highlight the importance of utilizing peer-reviewed literature to gain an education on a topic.

               Scientific research is crucial to a comprehensive understanding of any chemical, especially those that are obscure.  As humans in day-to-day life, we tend to be stubbornly biased and in many cases blindly defend or oppose one viewpoint with strong conviction based on our preconceived notions.  This concept highlights the importance of one of the most crucial research associated variables; sample size.  We must remember that opinion, especially personal opinion, in reality equates to a sample size of one.  How comfortable would you feel going to a doctor who completely based his practice upon the physiology of one patient?  Or how about deciding on using a prescription medication that was only tested in one human subject?  The point here, really, is that research provides strength in numbers based on objective data.  That is why it is used to generate everything from the development of the next novel pharmaceutical to the shape of the beverage bottle you drink from. 

The goal of quantitative research is to limit subjectivity so we can garner an unbiased understanding on a topic.  In other words, we are trying to limit the influence of the opinionated nature of humans.  This is not to say that every study published on a given topic is perfect and should be free of scrutiny, but when available, scientific studies are a much more dependable source of information than opinion.

               In regard to the natural vs. unnatural argument, two thoughts must be considered; 1the fact that toxins are readily abundant in nature, and 2the relevance of quantity consumed.  It seems common sense that one wouldn’t break the vial in an old mercury thermometer and attempt to drink from it, yet mercury is a natural element.  In fact, mercury poisoning is the sole reason most common thermometers now contain alcohol or Galinstan.  The same holds true for certain elements on the periodic table, they are known to be highly toxic.  More specific to our discussion, many of the foods we consume on a daily basis contain natural toxins that are either degraded through cooking methods or aren’t present in large enough quantities to adversely affect health [1].  The last point directly leads to the second concept of quantity.

               Quantity is one of the most important factors when discussing the safety of a compound in human health.  This may seem obvious for pharmaceuticals but there also exist very specific ranges of macro- and micronutrients that promote optimal health, while exceeding or falling short of these ranges can lead to serious health complications or even death.  Consider the well established importance of minerals like Calcium, Zinc, and Iron for bone health, oxygen transport, immunity, cellular hydration, optimal hormone production, etc…  If you exceed the requirements (significantly) of any of these elements they become toxic and cause symptoms such as:  vomiting, diarrhea, tissue damage, and in certain cases death.  Furthermore, consider complications resulting from chronically elevated blood glucose like neuropathy, hypertension, glaucoma, and renal failure.  So even the macronutrients we consume every day can be toxic.  The take home point being that natural is not always synonymous with safe.

               Please keep in mind these points discussed as they will be alluded to in our ensuing discussion on Sucralose.


               Sucralose, like many other artificial sweeteners, is cited as being discovered accidentally.  In 1975, a British sugar company named Tate & Lyle was researching alternative uses of sucrose in collaboration with King’s College in London where halogenated sugars were being synthesized and tested.  One of the graduate students, Shashikant Phadnis, misunderstood the request to test the chlorinated sugars and instead tasted them.  This ultimately led to the discovery that many chlorinated sugars are exponentially sweeter than table sugar (sucrose).  In fact, Sucralose is 600 times sweeter than sugar, so extremely minute quantities (relative to sucrose) can be used to sweeten foods and beverages [2-3]. 


               Sucralose is identical in structure to sucrose aside from the exchange of three chloro groups (-Cl) for three hydroxyl groups (-OH) at locations on the compound.


These changes account for a similar but distinct interaction of Sucralose with taste receptors in comparison sucrose.  To explain this concept, generalized characteristics of sweet taste perception via taste receptors will be provided.  It must be noted though, that the science of taste is incredibly complex and is yet to be completely resolved. 

               The perception of sweetness initiates when molecules bind to a specific G- coupled protein receptor (receptors that create an internalized chemical signal in response to extracellular stimuli) on the surface of taste buds.  The specific receptor for sweetness has been named T1R2-T1R3 as it is a complex formed of two protein subunits each with their own specific binding sites.  Due to the numerous binding sites (at least four are believed to exist) of the T1R2-T1R3 complex, it can accommodate a wide array of compounds, even macromolecules such as proteins can produce sweet taste by receptor interactions.[5]  Upon substrate binding to this complex, adenylyl cyclase is signaled resulting in the formation of the second messenger cAMP (cyclic adenosine monophosphate).  cAMP signaling activates ion channels on the cell membrane resulting in calcium influx, potassium efflux, and ultimately the activation of nerve fiber synapses which carry signals to the brain.[6]  The neurotransmitter serotonin is believed to be responsible for the modulation of sweet taste in humans.[7] 

The simplest proposed model of how compounds interact with the sweet receptor, of which recent models still encompass, involves three active sites denoted as the AH, B, and X regions.  The two main binding regions are hydrogen bond forming through their zwitterionic states.  The AH region is a proton donor, the B region a proton acceptor, and the X region is a hydrophobic binding pocket which generally interacts with the most nonpolar area of the compound rather than a specific atom or group.[2-3, 5, 8]  For a sweet molecule to interact with this receptor it must possess a complementary pair of hydrogen bond (or proton) donors and acceptors spaced at specific distances apart.  Furthermore, sweetness tends to positively correlate to hydrophobicity of a compound.  There appears to exist a threshold for this “rule” though, as after a certain point, increases in hydrophobic groups will lead to bitterness.[9]   Illustrations have been provided below to better reinforce these concepts.


Figure 1:  Simplified Illustration of AH/B interaction between sweet compound and receptor.





Most recent macrostructure model of the sweet taste receptor and its numerous interactions and binding sites for differing compounds.  Adapted from:  Temussi, P., The Sweet Taste Receptor: A Single Receptor with Multiple Sites and Modes of Interaction, in Advances in Food and Nutrition Research, L.T. Steve, Editor. 2007, Academic Press. p. 199-239.

               Again, general ideas are known and widely accepted for the function of the sweet receptor but its structure is yet to be completely resolved.  As such, a hypothesis of how sucralose binds with the sweet receptor based on information currently available (and previously discussed) is provided below.



 Figure 3:  Crude representation of Sucralose binding to taste receptor as suggested by Knight[2]

Sucrose and Sucralose are believed to bind to the taste receptor similarly, which inevitably leads to the question:   What is unique about Sucralose (or, indirectly, why Chlorine)?  Chlorine is part of Group 17 on the periodic table and, consequently, is a halogen.  Halogens are highly reactive elements due to their strong electronegativities (affinity to attract electrons from other atoms).   Conversely, they form highly stable compounds because they bind so strongly with reactants they limit the ability for further interactions to take place.  The relatively high electronegativity of chlorine also is a likely explanation for why sucralose leads to an exponentially sweeter taste on a gram per gram basis vs. sucrose (higher electronegativity=stronger interaction/binding with taste receptor).   Through the investigation on halogenated sugars done in 1989 at Queen Elizabeth College, it was determined that chlorine and bromine were the most effective halogens at eliciting pleasant, sweet tastes.  Furthermore, it was found that the chlorine and fluorine substituted sugars allowed the compound to possess higher water solubility.  The idea of fluorine substitution was quickly abandoned though, as it was not as sweet as the chlorinated version and fluorine in general is highly unstable and difficult to work with.  Ultimately it was determined that the most promising of the halogen substituted sugars was the trichloro- version (Sucralose) as it possessed the most sugarlike taste and exceptional stability at wide pH and temperature ranges.[2]

            Hopefully this introduction has provided you with a greater understanding on the rationale and biochemistry behind Sucralose.  Additionally, it was intended to help you formulate a more well rounded opinion on food products and/or supplements.  Next month, in part II, we will focus upon Sucralose metabolism and the studies that have analyzed its safety.


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