332

23

Regulatory Networks

the expressed enzymes, and it is of major interest to examine correlations between

expression data and metabolite data. ³⁹

Metabonomics is a subset of metabolomics and is defined as the quantitative mea-

surement of the multiparametric metabolic responses of living systems to pathophys-

iological stimuli or genetic modification, with particular emphasis on the elucidation

of differences in population groups due to genetic modification, disease, and environ-

mental (including nutritional) stress. In the numerous cases of diseases not obviously

linked to genetic alteration (mutation), metabolites are the most revealing markers

of disease or chronic exposure to toxins from the environment and of the effect of

drugs. As far as drugs are concerned, metabonomics is effectively a subset of the

investigation of the absorption, distribution, metabolism, and excretion (ADME) of

drugs.

Metabonomics usually includes not only intracellular molecules but also the com-

ponents of extracellular biofluids. Of course, many such molecules have been anal-

ysed in clinical practice for centuries; the novelty of metabonomics lies above all

in the vast increase of the scale of analysis; high-throughput techniques allow large

numbers (hundreds) of metabolites to be analysed simultaneously and repeat mea-

surements can be carried out in rapid succession, enabling the temporal evolution

of physiological states to be monitored. The concentrations of a fairly small number

of metabolites has been shown in many cases to be so well correlated with a patho-

logical state of the organism that these metabolite concentrations could well serve

as the essential variables of the organism, whose physiology is, as we may recall,

primarily directed toward maintaining the essential variables within viable limits (cf.

Sect. 3.2).

Metabonomics is being integrated with genomics and proteomics in order to create

a new systems biology, fully cognizant of the intense interrelationships of genome,

proteome, and metabolome; for example, ingestion of a toxin may trigger expression

of a certain gene, which is enzymatically involved in a metabolic pathway, thereby

changing it, and those changes may, in turn, influence other proteins, and hence (if

some of those proteins are transcription factors or cofactors) gene expression.

23.12 Data Collection

The basic principle is the same as in genomics and proteomics: separation of the

components followed by their identification. Unlike genomics and transcriptomics,

metabonomics has to deal with a diverse set of metabolites, which are in some sense

even more varied than proteins (which have the common feature of being all polypep-

tides). Typical approaches are to use chromatography to separate the components one

is interested in and mass spectrometry to identify them. Alternatively, high-resolution

nuclear magnetic resonance spectroscopy can be applied directly to many biofluids

and even organ or tissue samples

39 These correlations are crucial for understanding the links between genome and epigenetics.