Urinary Porphyrins for the Detection of Heavy Metal and Toxic Chemical Exposure

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Chapter 29 Urinary Porphyrins for the Detection of Heavy Metal and Toxic Chemical Exposure

image Introduction

Toxic chemicals affect human biochemistry at any level of long-term exposure. Fortunately, the body has mechanisms for transforming, eliminating, or compartmentalizing the many toxic chemicals encountered over a lifetime. Nonetheless, these “safety” mechanisms may be inadequate or even inappropriate in modern industrialized society, especially for susceptible people such as the elderly, individuals with poor nutritional habits, and others who are physiologically stressed.1,2

Recognizing and identifying offending chemical(s) can present a difficult challenge for the clinician. Many chemicals exert their effect at such low concentrations that they escape detection except by very sophisticated laboratory methods. Although measuring effects of toxicity by observing symptoms is a time-honored procedure, determination of the actual toxicant often requires the use of laboratory methods that measure biomarkers, which are specific indicators of the toxicant’s action.

Porphyrins measured in urine serve as such a biomarker. Porphyrins are particularly well suited as biomarkers for two reasons. First, they are produced in the highly active heme pathway, so any disturbance tends to cause rapid and relatively large accumulations of intermediates. Second, some of the enzymes of the porphyrin-producing pathway are highly sensitive to the presence of various toxins, and they are rapidly turned over. Their short half-lives of minutes or hours cause a demand for rapid synthesis in response to changing environmental signals. The enzymes normally associate with nutrient metal ions to produce heme and cobalamin (and, in plants, chlorophyll), sometimes called the pigments of life.3

The presence or elevation of various urinary porphyrin species can flag a potentially toxic condition. Metals and other toxic chemicals with prooxidant reactivity can inactivate porphyrinogenic enzymes, deplete glutathione and other antioxidants, and increase oxidant stress, all of which lead to damage to membranes, enzymes, and other proteins in cells.4,5 In addition, porphyrinogens (precursors to porphyrins in the reduced state) themselves are easily nonenzymatically oxidized to porphyrins by toxic metals such as mercury. Thus, the distribution pattern of porphyrins in the urine serves as a functional fingerprint of toxicity.6

The utility of urinary porphyrin measurement as a diagnostic tool is not new; its use has been documented in the literature since 1934. Specific diseases collectively known as the porphyrias, which can be inherited or acquired (e.g., acute intermittent porphyria, porphyria cutanea tarda, variegate porphyria), are often diagnosed with the aid of information about the distribution profile of individual porphyrin species in human urine.

image Definitions

Porphyrins are oxidized by-products that have escaped from the heme biosynthetic pathway, an essential pathway occurring in all nucleated mammalian cells. Heme is the all-important iron-binding molecule essential for the proper function of many proteins, including hemoglobin (oxygen transport), cytochrome c (energy production), and cytochrome P-450 (detoxification). Biosynthesis of heme involves eight enzymes (Figure 29-1), five of which produce intermediate molecules that are collectively called porphyrinogens. Some porphyrinogens escape the intracellular pathway to become oxidized by other cellular processes to porphyrins. In turn, some porphyrins are excreted in urine and feces.

The different molecular species of porphyrins that occur in the urine of healthy individuals form a predictable, characteristic pattern. An elevation of one or more porphyrins is designated porphyrinuria. The term porphyria