Tag: metabolites

Genetic Variations Influence Drug Metabolism in Patients of African Descent

Photo by Agung Pandit Wiguna

Investigators have identified new genetic variations that affect gene expression in the liver cells of patients of African ancestry, findings that provide insight into how drugs are metabolised differently in different populations, according to a study published in The American Journal of Human Genetics.

Expression quantitative locus (eQTL) studies use an individual’s genomic and transcriptomic data to uncover unique genetic variants that regulate gene expression. However, people of African descent have not been well represented in these databases.

Having this comprehensive, multiomic data is key to uncovering the mechanisms that regulate an individual’s genome and understanding how different groups of people respond to drugs differently, which can improve treatment strategies, according to Minoli Perera, PharmD, PhD, associate professor of Pharmacology and senior author of the study.

“We don’t have data from any historically excluded populations to run these analyses, so a big motivation of my lab is to create data in African ancestry populations so that they are represented in multiomics,” said Perera.

In the current study, the investigators treated hepatocytes from liver tissue samples from African American patients with six FDA approved drugs: Rifampin, Phenytoin, Carbamazepine, Dexamethasone, Phenobarbital and Omeprazole.

The investigators then performed whole-genome genotyping and RNA sequencing on primary hepatocytes treated both with and without the drugs. They also mapped eQTLs, or single-nucleotide polymorphisms (SNPs) affecting gene expression, in the liver cells.

From this comprehensive analysis, they uncovered varying transcriptional changes in the cell lines across the different drug treatments and identified NRF2 as a potential gene transcription regulator.

“NRF2 has been already identified as a very important transcription factor for drug metabolism, but this is a much more comprehensive way to look at it,” Perera said.

The investigators also discovered nearly 3000 genetic variants that affect how well hepatocytes respond to external stimuli, including drugs, which the investigators called drug response eQTLs, or reQTLs. Notably, they discovered reQTLs for drug-metabolising genes such as CYP3A5.

Most individuals of European ancestry carry a specific genetic variant in CYP3A5 which results in no/low CYP3A5 enzyme, whereas individuals of African ancestry carry that variant at a lower frequency. According to Perera, this is a problem because most participants that are recruited for clinical trials are of European ancestry, and the findings from these trials directly inform how often and how much of a drug should be prescribed to all patients, regardless of their ancestry.

“When you test drugs in a group of people with limited diversity, and then say this is the dose, this is how fast it’s metabolised, this is how often you dose the drug and then you give this medication to the entire U.S. population, we don’t know for sure how accurate those measures are, and that’s just with one variant. Other variants that may influence how much or how little we up-regulate these important enzymes,” Perera said.

Perera said her team is now expanding their work by increasing the number of hepatocytes from African American participants they’re studying and incorporating other types of omics techniques, such as epigenetic profiling.

“Almost exclusively we’ve done epigenetic screenings in European populations, so what can we find in the epigenome that’s important for African Americans. Also, because there’s more genetic variation in individuals of African descent, would that change the epigenome in ways that we aren’t able to see in Europeans,” Perera said. “We hope that what we’re doing can help annotate new studies coming along for African ancestry populations.”

Source: Northwestern University

Antifungal Compound Discovered in Ant Farms

Researchers in Brazil have discovered an antifungal compound by bacteria living in ant farms, which may have medical applications.

In the fungal farms where attine ants tend as their food source, Pseudonocardia and Streptomyces bacteria produce metabolites which shield the crop against pathogens. Curiously, these metabolites vary across geographic locations.

Attine ants are a type of ant which grow and harvest fungus for food, and are only found in the Western Hemisphere. They first evolved from a common Amazonian ancestor some 50 million years ago, giving rise to some 200 species of ants spread across South and Central America, which share common farming practices. The bacteria at these farms have a symbiotic relationship where they defend against fungi such as Escovopsis in exchange for food.

These metabolites vary considerably, suggesting a fragmented history. Searching a number of ant nests spread across a large geographical area, the researchers discovered that two thirds of the Pseudonocardia strains were producing the same metabolite. They named this newly discovered metabolite attinimicin.The study was the first one where a common, specialised metabolite produced by ant-associated bacteria was found across geographic locations.

Attinimicin inhibited fungal parasites while not harming the fungal crop, but only in the presence of iron. It proved as effective in treating Candida albicans infections in mice as a clinically used azole-containing antifungal. This means that the metabolite could have clinical applications. Attinimicin was shown to have a similar structure to two other metabolites produced by Streptomyces, suggesting the responsible genes have a common evolutionary origin.

Source: News-Medical.Net

Journal information: Fukuda, T.T.H., et al. (2021) Specialized Metabolites Reveal Evolutionary History and Geographic Dispersion of a Multilateral Symbiosis. ACS Central Science. doi.org/10.1021/acscentsci.0c00978.

Depression May be Influenced by Metabolism

A study by researchers from University of California San Diego School of Medicine and from the Netherlands, has shown that major depressive disorder (MDD) may be predicted by metabolism, in the form of certain metabolites.

MDD is one of the most common disorders, with a lifetime prevalence of 20.6% in the United States. For those with recurrent major depressive disorder (rMDD), the risk is 80% over five years.

MDD is characterised by any combination of feelings of sadness or hopelessness, anger or frustration, loss of interest, sleep disturbances, anxiety, slowed or difficulty thinking, suicidal thoughts and unexplained pain such as backaches.

“This is evidence for a mitochondrial nexus at the heart of depression,” said senior author Prof Robert K Naviaux, at UC San Diego School of Medicine. “It’s a small study, but it is the first to show the potential of using metabolic markers as predictive clinical indicators of patients at greatest risk—and lower risk—for recurring bouts of major depressive symptoms.”

Recruiting 68 participants who were in remission for rMDD and not on antidepressants, the researchers found a range of molecules in participants’ blood that were up to 90% predictive of relapse in 30 months. The most predictive molecules consisted of certain lipids and purines.

Purines are produced from molecules such as ATP and ADP (major cellular energy storage molecules), and also have a role in signalling in stressed cells.The researchers found that in subjects with rMDD, certain metabolites in six metabolic pathways resulted in the alteration of key cellular activities.

“The findings revealed an underlying biochemical signature in remitted rMDD that set diagnosed patients apart from healthy controls,” Naviaux said. “These differences are not visible through ordinary clinical assessment, but suggest that the use of metabolomics—the biological study of metabolites—could be a new tool for predicting which patients are most vulnerable to a recurrence of depressive symptoms.”

Source: Medical Xpress

Journal information: Roel J. T. Mocking et al. Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence, Translational Psychiatry (2021). DOI: 10.1038/s41398-020-01182-w