Peroxidation of Lipids and Proteins

Some chemicals exist as free radicals or generate free radicals during their metabolism. Free radicals are highly reactive and will oxidize proteins or lipids, changing their structure. The developmental toxicity of hydroxyurea is at least partially mediated by free radicals (DeSesso 1979; DeSesso and Goeringer 1990; DeSesso et al. 1994) and that of niridazole appears to be entirely mediated by radical production (Barber and Fantel 1993). Physical agents such as ionizing radiation also produce this type of oxidative damage, as does the body itself during reperfusion after an ischemic episode. See recent reviews by Fantel (1996) and Wells and Winn (1996) for a more detailed discussion on this topic.

Interference with Sulfhydryl Groups

Sulfhydryl groups often play an important role in maintaining the tertiary structure and, therefore, the biological activity of proteins, especially in the disulfide linkages of secreted proteins. In some proteins, sulfhydryl groups are functional groups of the active (catalytic) site. Metals like mercury and cadmium are examples of developmental toxicants that cause oxidative stress and bind strongly to sulfhydryl groups and interfere with function (see reviews by Clarkson 1993; Stohs and Bagchi 1995; Quig 1998). The mechanism of one form of mercury, methylmercury, toxicity is described in detail below.

Inhibition of Protein Function

This is a broad category. Protein function occurs at catalytic sites (catalysis), regulatory sites (regulation of protein activity), macromolecule binding sites (such as specific DNA binding), or protein-protein association sites (as in aggregation of ribosomal proteins).

Some agents interfere with enzymes whose catalytic function is important in development, somewhat similar to an antagonist binding to a receptor. For example, methotrexate, a cancer chemotherapeutic agent mimics a substrate of dihydrofolate reductase, and its inhibitory binding results in a functional folate deficiency, which is developmentally adverse (DeSesso and Goeringer 1991, 1992). The mechanism is described in more detail below. Angiotensin-converting-enzyme (ACE) inhibitors are another example of agents that interfere with development by blocking enzyme action. These drugs block the conversion of angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictive agent controlling blood pressure in adults. In the human fetus and neonate, it is needed to maintain renal perfusion and glomerular filtration. When angiotensin II levels are reduced in the fetus, glomerular filtration pressure and urine production are



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