Metabolomics plays an essential role in toxicological research by providing a detailed analysis of altered metabolic pathways that are targeted by harmful chemicals. It also helps researchers and key players in the medical field to understand the mechanism of harmful chemicals.
Image Credit: Rattiya Thongdumhyu/Shutterstock.com
Metabolomics is the study of metabolites. It aims to provide a comprehensive analysis of the biochemical and physiological status of the body, as well as changes in metabolic profile in response to internal and external factors.
Such information subsequently facilitates the discovery of biomarkers that are associated with pathologic conditions. These biomarkers also play vital roles in mapping the effectiveness of drug therapies through various metabolomics approaches.
Advantages of metabolomics in toxicology
The main advantage of using metabolomics in toxicology is that alterations in metabolism are ‘downstream’ events to those that occur at genetic, transcriptomic, and proteomic levels. Thus, metabolomics facilitates the understanding of direct cellular phenotypes that are induced by toxic insults.
In addition, since changes in extracellular metabolites mirror the intracellular metabolic scenario, metabolomics analysis of biological fluids (urine or blood) obtained through non-invasive or minimally-invasive techniques suffices for the evaluation of target organ toxicities.
Another important benefit of metabolomics is that information on a large number of metabolites can be obtained through a single measurement, and oftentimes basic requirement for rapidly understanding the level of drug toxicity. Moreover, large-scale screening of drugs or chemical compounds can be achieved through in vitro metabolomics approaches.
One important use of in vitro metabolomics, which employs cell lines, primary cells, co-cultures in 2D or 3D format, etc, is to predict toxicological patterns of unknown chemicals in the biological system using known reference chemicals.
Such analysis starts with the comparison of a metabolic profile of a known reference chemical with its toxicological profile in vivo. This allows for the generation of a ‘toxicity pattern,’ which defines the metabolic profile related to a distinct toxicological endpoint.
Afterward, the degree of overlap is calculated by aligning the metabolic profile of the unknown chemical with the toxicity pattern. The data are used to predict the toxicological pattern of an unknown chemical;
However, the major challenge associated with the use of in vitro metabolomics is the extrapolation of in vitro data to in vivo settings in order to get optimal information on drug efficacy and drug safety.
How metabolomics is used in toxicology
The advancement of metabolomics has made it routinely and extensively useful in many toxicology-related fields.
Drug toxicity assessment
Metabolomics has remarkable potential in screening drug-induced cellular or organ toxicity. Rapid assessment of biological samples, especially biofluids, together with mathematical and statistical analysis (chemometrics) of obtained data serves as a powerful platform for drug safety assessment.
For instance, if a drug or chemical causes hepatic toxicity by inducing cellular oxidative stress, metabolomics analysis of the drug-exposed biological sample can provide direct information about metabolites that are straightforward indicative of the oxidative stress.
It can also specify metabolites that are considered as known biomarkers of hepatic injury, thus indicating hepatic pathology. In addition, metabolomics analysis can also provide information about metabolites that are indirectly associated with toxicity.
Drug safety assessment
Metabolomics has several advantages over conventional clinical pathology assessment in terms of capturing a broad spectrum of metabolic scenarios. For instance, a study investigating an unknown compound has revealed that the compound increases serum cholesterol levels.
Upon the utilization of metabolomics, it has been observed that, apart from cholesterol, the compound also increases several phytosterols, indicating that the elevated cholesterol is an outcome of the sterol absorption in the gut. Such findings clearly suggest that metabolomics has a much higher potency in terms of defining exact toxicological endpoints.
Defining the mechanism of action for a drug
To effectively assess the toxicity aspect of a drug or chemical, it is important to understand its mode of action. In addition, to portray drug-induced toxic phenotypes, metabolomics also serves as a good platform to investigate how a particular drug exerts its effects in the cellular backdrop.
Challenges of metabolomics in toxicology
Before using metabolomics as a rigorous tool for assessing drug toxicity and its mode of action, technical and biological variations associated with the data should be taken into consideration.
Technical variations, which mainly come from sample preparation, analytical procedure, or separation and detection of metabolites, could be resolved by using standard operating procedures (SOP) and proper quality control measures.
To negate any biological variations which are common when using different experimental animal models, standard operating procedures should be established for each separate system.
Biological variability should be addressed seriously, as it can potentially generate false positive or false negative data by hiding subtle but important information.
Sources:
- Sun, J. (2012). Metabolomics in Drug-induced Toxicity and Drug Metabolism. Journal of Drug Metabolism & Toxicology, 3, e111.
- Robertson, DG, Watkins, PB, & Reily, MD. Metabolomics in Toxicology: Preclinical and Clinical Applications. Toxicological Sciences, 120(1), S146–S170.
- Ramirez et al (2013). Metabolomics in Toxicology and Preclinical Research. ALTEX, 30(2), 209–225.
Further Reading