Mahilum, Nino Angelo Joaquin G.
BIO1106 Sec-5
Department of Medical Technology
Biochemistry
A Case Study on Proteins
The Problem
Glutathione has a whitening impact on the skin that is seen as a side effect.
According to research, glutathione inhibits tyrosinase, which affects skin
pigmentation (Dilokthornsakul et al., 2018). The interaction of glutathione with
tyrosinase has been hypothesized in many ways (Dilokthornsakul et al., 2018):
1. it inactivates tyrosinase by chelating the copper ion;
2. it prevents tyrosinase from reaching the premelanosome;
3. it scavenges free radicals and peroxide, preventing tyrosinase activation; and
4. it shifts the skin pigmentation pathways from eumelanin to phaeomelanin.
The various glutathione products for skin whitening are administered topically,
orally, and parenterally (Dilokthornsakul et al., 2018). Knowing the mechanism of
action of glutathione, we need to assess the efficiency and safety of each route of
glutathione administration.
Table 1. Structure and properties of glutathione
Structure
Properties
Mass:
307.3260
g/mol
logP :
-0.7240
H-bond acceptors:
9
H-bond donors:
5
Rotatable bonds:
11
PSA:
197.6200
Refractivity:
70.3674
Atoms:
37
Rings:
0
Heavy atoms:
20
Hydrogen atoms:
17
Heteroatoms:
10
Chiral centers:
2
R/S chiral centers:
2
I. Guide Questions
1. What is the bioavailability (high or low) of glutathione when applied topically? Intravenously? Explain
why. (5pts)
Answer:
Glutathione bioavailability, when applied topically, has low bioavailability because absorption process is
still required for this method. Such methods such as creams or pills are required to be absorbed by the
skin or pass through the liver to be distributed throughout the body, therefore, some of the drug will
either be destroyed by the liver or unable to be absorbed by the skin (AMBOSS, 2019). On the other hand,
intravenous administration is said to always have a high 100% bioavailability (PhysioPathoPharmaco,
2019) since the entirety of the drug reaches circulation and thus, utilized entirely.
2. Using Table 1, predict the oral bioavailability of glutathione. Explain why using the properties you used
to assess its oral bioavailability? Hint: you may read this article DOI: 10.1089/cmb.2019.0323 (5pts)
Answer:
Predicting oral bioavailability utilizes the Rule of 5 by Christopher Lipinski, a medical chemist at Pfizer.
He states that the following characteristics of the molecule must be:
-
Less than 500 daltons or g/mol
-
Has no more than 5 hydrogen bond donors
-
No more than 10 hydrogen bond acceptors
-
Partition coefficient or log P of not greater than 5
all of which are important in determining the solubility, absorption, and permeation of the drug (Lipinski
et al., 2001). Using the data found in Table 1, it is found that there is:
-
307.3260 g/mol
-
5 H-bond donors
-
9 H-bond acceptors
-
log P of -0.7240
all of which satisfies the Rule of 5, therefore, it is estimated to be orally bioavailable.
3. What is the importance of bioavailability to assess the efficiency of glutathione? (2 pts)
Answer:
Bioavailability could dictate the dosage which a drug needs to effectively spread throughout the body. If
a drug has low bioavailability, it could mean that their needs to be a higher dosage to accommodate the
loss brought by metabolism. If there is a high bioavailability, then their needs to be precise dosage because
a lack or abundance of the substance may lead to harmful effects or the drug not working effectively.
4. How does glutathione enter the cell? (3 pts)
Answer:
Glutathione is made in the cytosol and there are 3 ways it may be present in the cell. The first is through
the De novo synthesis catalyzed by glutamate cysteine ligase and glutathione synthetase and addition of
ATP. The second is through the regeneration of oxidized glutathione into reduced glutathione by
glutathione reductase with the addition of NADPH. Lastly, it is also produced from recycling cysteine from
conjugated glutathione by Gamma-glutamyl transpeptidase with addition of NADPH (Pizzorno, 2014)
5. Using your knowledge about the absorption, distribution, and metabolism of glutathione in the different
routes, think of a possible scenario that you will not benefit from taking glutathione. (Hint: you may
describe these scenarios by the dosage of glutathione used). (15 pts)
Answer:
If for example a glutathione concoction made into a topical cream which is to be used by lathering onto
the skin, is made from glutathione molecules with a partition coefficient of more than 2-3, it then indicates
that they are more hydrophobic, thus they may not be able to penetrate the skin, specifically the stratum
corneum with interactions of lipophilic molecules with its higher water content (Ellison et al., 2020). This
could then hinder its effectivity since that glutathione unabsorbed would then be stuck outside with the
dead skin cells, becoming useless. If there is only an irrelevant amount of glutathione then the desired
effect of whitening through inhibition of melanin synthesis may not be met, thus, unbeneficial.
References:
AMBOSS: Medical Knowledge Distilled. (2019, September 14). Pharmacokinetics - part 1: Topical and
systemic drugs [Video]. Youtube. Retrieved December 1, 2021, from
https://www.youtube.com/watch?v=x_JaFhWlOZo.
Ellison, C. A., Tankersley, K. O., Obringer, C. M., Carr, G. J., Manwaring, J., Rothe, H., Duplan, H., Géniès,
C., Grégoire, S., Hewitt, N. J., Jamin, C. J., Klaric, M., Lange, D., Rolaki, A., & Schepky, A. (2020,
September 1). Partition coefficient and diffusion coefficient determinations of 50 compounds in
human intact skin, isolated skin layers and isolated stratum corneum lipids. Toxicology in Vitro.
Retrieved December 1, 2021, from
https://www.sciencedirect.com/science/article/pii/S0887233320305403.
Lipinski , C. A., Lombardo, P. J., Dominy, F., & Feeney, B. W. (2001, March 1). Experimental and
computational approaches to estimate solubility and permeability in drug discovery and
development settings. Advanced drug delivery reviews. Retrieved December 1, 2021, from
https://pubmed.ncbi.nlm.nih.gov/11259830/.
PhysioPathoPharmaco. (2019, February 22). Bioavailability and first pass metabolism [Video]. Youtube.
Retrieved December 1, 2021, from https://www.youtube.com/watch?v=BQQns7RAUzA.
Pizzorno, J. (2014, February). Glutathione! Integrative medicine (Encinitas, Calif.). Retrieved December 1,
2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684116/.