Humboldt State University ® Department of Chemistry

Richard A. Paselk

Chem 451

Biochemical Toxicology

Spring 2010

Lecture Notes:: 2 February

© R. Paselk 2008
 
     
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Enzymes

Enzymes are protein-based catalysts of incredible power. Can get rate enhancements of over 1013 compared to uncatalyzed reactions at the same temperature! Enzymes are also specific. The result is that enzymes "choose" the chemistry which occurs in living organisms. Many toxins function by interfering with normal enzyme operation. And the most potent natural toxins are enzymes.

Enzymes have a limited number of functional groups available to aid in catalyzing reactions, which are the functional groups found on the 20 amino acids used in synthesizing proteins:

structural diagram of carboxylate, alcohol, amine, thiol, phnol and imidazole functional groups.

Many toxins damage enzymes by reacting with one or more of these functional groups.

Metabolic Pathways

Metabolic pathways describe the flow of metabolites through an organism. The handout gives an overview of a few of the most important and common pathways in biochemistry.

Dose-Response Relationships

Dose-response relationships provide a way of quantifying toxicity. As noted earlier, all substances are toxic, quantity distinguishes harm from harmless or even benefit.

Biomarkers

Biomarkers in toxicology are biological measures of response to toxic exposure. they can be categorized into three groups:

Biomarkers of Exposure - Can simply measure the apparent exposure, e.g. concentration in air or water or amount applied to skin. But the actual exposure is affected by processes of absorption etc. so true exposure may be much different.

Even measures of internal concentration can be misleading since toxins often act on a specific organ, cell type or tissue. In this case what matters is the exposure of that portion of the organism. Can also get other complications, such as the "toxin" may not even be toxic, rather a metabolite may be the true poison. Or the toxin may react with a protein or other cell structure which is the true toxin and thus reflects the true dose.

In theory these can all be measured as biomarkers, but we generally do not know that level of detail at this time, so we often use environmental levels of exposure as proxi for the true dose.

Biomarkers of Responese - we can measure many different types of responses to toxins as will be seen in later chapters of the book (Chap. 6): tissue lesions, Cellular Toxicity, Pharmacological Effects, Teratogenesis, Immunotoxicity, Genetic Toxicity and Chemical Carcinogenosis.

Today a variety of biomarkers based on molecular biology techniques have been added to the mix as measures of response including: genomics, transcriptomics, proteomics and metabolomics. These techniques often require in turn the methods of bioinformatics to pick out patterns and make sense of the complex "omic" results.

Biomarkers of Susceptability - susceptability to toxins vary widely over organisms and even individuals due to factors such as enzyme deficiencies and variation in repair systems.

Note that biomarkers can and are used in attempting to assess risk to various toxins.

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© RA Paselk 2001