Introduction
Caffeine is one of the most widely utilized behaviorally active substances globally. Caffeine is a psychoactive drug that influences various neurotransmitter systems, such as activating noradrenaline neurons and antagonizes adenosine receptors. Adenosine downregulates the central nervous system. Therefore, inhibiting its function, caffeine leads to the activation of the brain’s medullary, vagal, vasomotor, and respiratory centers (National Center for Biotechnology Information 2022). Following consumption, caffeine is metabolized by the liver to release the main caffeine metabolite paraxanthine, methylated xanthine, and methyluric acids (DePaula & Farah, 2019). As caffeine influences the brain systems, it leads to increased alertness hence appropriate for performance enhancement when alertness is low. Structurally caffeine is a methylxanthine alkaloid found in several plant parts such as seeds, barks, and leaves of coffee, tea, and other plants. It has a purine structure, xanthine, similar to adenosine and hence functions as an adenosine receptor antagonist. The structure contains a pyrimidine ring connected to an imidazole ring (DePaula & Farah, 2019). This paper presents a genetic control of caffeine and its chemical interaction, its function in the body, and its solubility and polarity.
The Genetic Control of Caffeine and Chemical Interaction of Caffeine and Its Related Bonds
Various individuals react differently to caffeine; for example, some experience anxiety while others experience sleep disturbance and lack of sleep (Yang et al., 2010). Accordingly, differences in caffeine metabolism occur at the pharmacokinetic, caffeine metabolism and pharmacodynamics interaction with cellular components, therefore, playing a part in the variability in quality and drug magnitude of the consumed caffeine. Additionally, genetic factors influence how responses to caffeine, short term or long term, influence other areas that caffeine impacts, such as rewarding functionality, anxiety sensitivity, personality traits, and addiction (Yang et al., 2010). A significant difference in the genetic influence of caffeine is the variation in the structure and functioning of the P-450 enzymes. The enzymes are the main catalytic drivers in caffeine metabolism that demethylates caffeine to form paraxanthine, theobromine, and theophylline. P-450 enzyme is encoded by CYP1A2 gene whose activity differs between individuals. Therefore, different individuals who possess variation in the enzyme P-450 gene may have varying caffeine clearance rates.
Caffeine intake is also linked to the upregulation of adenosine receptors such as A1, the primary target for caffeine, common and widely spread in the central nervous system. The effect of caffeine interaction with the receptor, inhibiting adenosine activity, enhances acetylcholine release, leading to arousal activities. The upregulation is linked to the resultant caffeine effects. In addition, adenosine influences other neurotransmitter systems such as glutamatergic neurotransmission through A1-A2A receptors and GABAergic and cholinergic systems through A2A. Therefore, variations in the individual’s receptors’ genetics and the genetic variation in the metabolic enzymes implicate the genetic control of caffeine (Yang et al., 2010). The differences also confer vulnerability to continued use of caffeine through the dopaminergic system, where the inhibition of adenosine receptors leads to increased dopamine and norepinephrine transmission (Cauli & Morelli, 2005).
Following consumption, caffeine is distributed to most tissues and body fluids, including sweat and urine. This process of absorption from the stomach and intestine takes about 45 minutes. Caffeine has limited binding to plasma protein and relative hydrophobicity, thus facilitating passage across cell membranes. Liver cells rapidly metabolize caffeine to form dimethyl and monomethylxanthines, dimethyl and monomethyluric acids, and uracil derivatives. The CYP1A2 enzyme is the main P-450 enzyme that metabolizes caffeine. Caffeine metabolism leads to the release of paraxanthine, the primary metabolite in plasma, and methylated xanthines and methyluric acids excreted in the urine (DePaula & Farah, 2019). The central role of caffeine is implicated in the brain, where it has an antagonist role on adenosine receptors. It acts both externally and internally on brain cells. Due to its purine structure, caffeine binds with adenosine and adenosine-related nucleosides receptors (Fisone et al., 2004). Intracellularly caffeine influences the Ryanodine receptor that are targets for cyclic ADP ribose and cAMP phosphodiesterase. The reduced activity of the inhibitive adenosine molecules leads to increased dopamine neurotransmitter activity that leads to caffeine’s stimulatory effects (Yang et al., 2010).
In addition, caffeine increases adrenaline levels and serotonin, increasing energy levels and changes in moods. In addition, paraxanthine increases lipolysis, which leads to increased fatty acid levels in the blood plasma. Theobromine leads to vasodilation, thus increasing the amount of oxygen and nutrients flowing to the brain. Adenosine leads to vasoconstriction of the afferent arterioles of the glomerulus; therefore, its inhibition counteracts the effect leading to vasodilation and renal output. Theophylline has a relaxation effect on the smooth muscles of the bronchi, enhancing breathing (DePaula & Farah, 2019).
The competitive inhibition between adenosine and caffeine disrupts nerve conduction through inhibiting impulse propagation at the postsynaptic cleft. This inhibition causes an increased release of epinephrine through the hypothalamic-pituitary-adrenal system. In turn, epinephrine as a ‘fight or flight’ hormone leads to increased blood pressure and its flow to the muscles, reduced flow to the internal organs, and an increase in blood glucose (Graham et al., 1994). In addition, the influence of cyclic AMP that facilitates intracellular messaging is positive in the presence of caffeine hence sustaining the impact of epinephrine. The activation also increases f-gastric acid restriction by activating the proton/potassium pump. Caffeine can also diffuse into cells, leading to the release of the stored calcium in the endoplasmic reticulum. Caffeine induces the released calcium that can initiate an action potential.
Caffeine Solubility
(Tavagnacco et al., 2012)
Caffeine’s solubility varies across various solvents. Due to its structure, methylxanthine, caffeine has low solubility; therefore, it is mixed with other compounds such as sodium benzoate in soft drinks. A study that determined caffeine solubility on several solvents showed that caffeine solubility decreased across chloroform, dichloromethane, acetone, ethyl acetate, water methanol, ethanol, and carbon tetrachloride. The solubility also increased with increased temperature (Shalmashi & Golmohammad, 2010). Caffeine has several types of functional groups with different hydration patterns and hydrophobic regions. Caffeine is partially polar because of the two carbonyl groups, O2 and O6, and the lone pair of electrons of the nitrogen (N9) serving as hydrogen bond acceptors (Tavagnacco et al., 2011).
Because the secondary amino groups are fully methylated and the monohydrate crystal structure, the bond water is only hydrogen linked to the nitrogen at the 9th position. However, the H9 also participates in hydrogen bonding with water, as observed in similar hydrogen groups of purines in nucleic acids (Tavagnacco et al., 2011). Also, in aqueous solutions, caffeine forms dimer segregation that involves two hydrophobic flat surfaces. Therefore, this aggregation reduces the surface available to interact with water molecules (Tavagnacco et al., 2011).
Conclusion
Caffeine is a heterocyclic aromatic compound purine, a methyl alkaloid, and has structural similarities with adenosine. It is found in seeds, leaves, and barks of several plants, including coffees and tea. Due to genetic differences in genes encoding caffeine metabolizing enzymes and receptor targets, people metabolize caffeine differently. In addition, continuous caffeine intake upregulates target receptors’ expression increasing their number and effects. Caffeine intake increases body metabolism and urine formation and enhances brain activity by antagonizing the inhibitory adenosine receptors. However, due to its purine structure, caffeine is partially hydrophobic and hence reduces solubility in water.
References
Cauli, O., & Morelli, M. (2005). Caffeine and the dopaminergic system. Behavioural Pharmacology, 16(2), 63-77. https://doi.org/10.1097/00008877-200503000-00001
DePaula, J., & Farah, A. (2019). Caffeine consumption through coffee: Content in the beverage, metabolism, health benefits and risks. Beverages, 5(2), 37.
Fisone, G., Borgkvist, A., & Usiello, A. (2004). Caffeine as a psychomotor stimulant: mechanism of action. Cellular and molecular life sciences : CMLS, 61(7-8), 857–872. https://doi.org/10.1007/s00018-003-3269-3
Graham, T. E., Rush, J. W., & van Soeren, M. H. (1994). Caffeine and exercise: metabolism and performance. Canadian journal of applied physiology = Revue canadienne de physiologie appliquee, 19(2), 111–138. https://doi.org/10.1139/h94-010
National Center for Biotechnology Information (2022). PubChem Compound Summary for CID 2519, Caffeine. Retrieved May 9, 2022 from https://pubchem.ncbi.nlm.nih.gov/compound/Caffeine.
Shalmashi, A., & Golmohammad, F. (2010). Solubility of caffeine in water, ethyl acetate, ethanol, carbon tetrachloride, methanol, chloroform, dichloromethane, and acetone between 298 and 323 K. Latin American applied research, 40(3), 283.
Tavagnacco, L., Engström, O., Schnupf, U., Saboungi, M. L., Himmel, M., Widmalm, G., Cesàro, A., & Brady, J. W. (2012). Caffeine and sugars interact in aqueous solutions: a simulation and NMR study. The journal of physical chemistry. B, 116(38), 11701–11711. https://doi.org/10.1021/jp303910u
Tavagnacco, L., Schnupf, U., Mason, P. E., Saboungi, M. L., Cesàro, A., & Brady, J. W. (2011). Molecular dynamics simulation studies of caffeine aggregation in aqueous solution. The journal of physical chemistry. B, 115(37), 10957–10966. https://doi.org/10.1021/jp2021352
Yang, A., Palmer, A. A., & de Wit, H. (2010). Genetics of caffeine consumption and responses to caffeine. Psychopharmacology, 211(3), 245-257.
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