Microbes and Medicines
The metabolism of drugs, and therefore their effects, can vary widely from person to person and attempts to understand the genetic and phenotypic reasons behind this have led to the rise of the field of pharmacogenomics. Unfortunately, not only can genetic differences result in altered drug metabolism but also environmental factors such as gut bacterial activity, disease, and age. To counter this fact a pharmacometabonomic approach has been suggested that takes into account measurements of metabolites and biomarkers prior to drug administration. In a recent study, published in PNAS, Dr. Jeremy Nicholson and his team used this approach to demonstrate that a person’s gut microbes can affect their ability to metabolize acetaminophen.
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In the study 99 healthy male volunteers provided urine samples before (predose) and after (postdose) being given 1000 mg of acetaminophen. The samples were then analyzed by NMR spectroscopy to identify endogenous metabolites in the predose samples and acetaminophen-related compounds in the postdose samples. Acetaminophen sulfate (S) and acetaminophen glucuronide (G) are two common metabolites of acetaminophen that are produced through two different metabolic processes and accounted for approximately 85% of the acetaminophen-related compounds detected in the urine samples. The relative contribution of either sulfonation or glucuronidation to acetaminophen metabolism is known to vary greatly between people thus the team was interested in any correlations between intersubject variations in the S/G ratio and intersubject variations in any predose metabolites.
In the analysis of the pre- and postdose metabolites only one significantly correlated with the variations in the S/G ratio—p-cresol sulphate (PCS), higher levels of which were associated with a lower S/G ratio. PCS is produced by the sulfonation of p-cresol which is a byproduct of the metabolism of tyrosine by colonic bacteria. The sulfonation of p-cresol occurs not within bacteria but within human tissue, such as the colonic mucosa and the liver, and is mediated by the same enzyme that sulfonates acetaminophen. Thus the results suggest that a high level of circulating PCS significantly decreases the ability of the body to sulfonate acetaminophen which could increase the risk of acetaminophen-induced liver damage.
Although this potential risk would need to be investigated further the finding also has consequences for various processes such as the metabolism of other drugs, the production of biomolecules (e.g. chondroitin sulphate, a component of cartilage), and the sulfonation-related modulation of various hormones and neurotransmitters as well as various diseases including hyperactivity in children and multiple sclerosis, which have both been associated with high levels of p-cresol and/or PCS. Overall, this study indicates that gut microbes could play a significant role in drug efficacy and adverse drug reactions and highlights once again the importance of the gut microbiome to humans in both health and disease. Indeed, the authors conclude that “assessing the effects of microbiome activity should be an integral part of pharmaceutical development and of personalized health care.”
Article:
T. Andrew Clayton, David Baker, John C. Lindon, Jeremy R. Everett, and Jeremy K. Nicholson. (2011). Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. PNAS, 106(34): 14728–14733.
DOI: 10.1073/pnas.0904489106
About the author: Ruth Warre is a freelance scientific writer and editor currently living in Toronto. She writes on a variety of subjects from microbiomes to neuroscience, in a variety of mediums from blogs to peer-reviewed articles.
