Introduction

Toxic chemicals, at any level of chronic exposure, affect human biochemistry. Fortunately, the body has mechanisms for transforming, eliminating or compartmentalizing many toxic chemicals encountered over a lifetime. Nonetheless, these "safety" mechanisms may be inadequate or even inappropriate in our modern industrialized society, especially for susceptible people such as the elderly, individuals with poor nutritional habits, and others who are physiologically stressed . One class of "textbook" toxic chemicals capable of subtle yet insidious health effects that may mimic other disorders, especially in children, is that of the heavy metals. Lead, mercury, arsenic, aluminum, and cadmium are well-documented examples. Chronic exposure to these metals often results in organ-specific accumulation, which compromises the physiology of that organ. Similarly, chronic exposure to organic chemicals such as herbicides, pesticides, industrial and manufacturing byproducts can have deleterious impact on the body"s biochemistry, resulting in decline of cellular function .

Identifying offending chemical(s) can present a challenge for the clinician. Many chemicals exert their effect at such low concentrations that they escape detection except by very sophisticated laboratory methods. While measuring effects of toxicity by observing symptoms is a time-honored procedure, a preferred approach is to use corroborative laboratory methods that measure biomarkers that are specific indicators of the toxicant"s action.

Porphyrins measured in urine serve as such a biomarker. 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 damaged membranes, enzymes and other proteins in cells . In addition, porphyrinogens (precursors to porphyrins in the reduced state) themselves are easily nonenzymatically oxidized to porphyrins by toxic metals such as mercury (Figure 1). Thus, the distribution pattern of porphyrins in the urine serves as a functional "fingerprint" of toxicity.

The utility of urinary porphyrins 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 porphryia, porphyria cutanea tarda, variegate porphyria), are often diagnosed with the aid of information regarding the distribution profile of individual porphyrin species in human urine.

Definitions

The different molecular species of porphyrins that occur in the urine of healthy individuals form a predictable, characteristic pattern. The alteration of the usual pattern of porphyrins caused by the elevation in one or more porphyrins is designated porphyrinuria. Porphyria, as a term, is reserved for primary conditions exhibiting specific clinical symptoms caused by an inherited defect in one or more of the heme biosynthetic enzymes. Porphyrinopathy is an umbrella term for any disorder in porphyrin metabolism.

The porphyrias have been classified in the literature in several different ways. Most commonly, porphyrias are presented in textbooks with specific biochemical reference to the principal enzyme deficiency (e.g. ALA dehydratase deficiency, etc.) and the site of the deficiency (i.e. hepatic, erythropoietic, or both). Other valid classifications arrange porphyrias according to symptomatology (neuropathic, dermatopathic or a mixed presentation of these symptoms) or by whether symptoms appear episodically (e.g., acute intermittent porphyria or chronically. It is also useful to organize porphyrias according to etiology (e.g., hereditary vs. acquired or toxicant-induced porphyria).

Background

Porphyrins are oxidized byproducts 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 2), five of which produce intermediate molecules that are collectively called porphyrinogens. Some porphyrinogens escape the intracellular pathway to become oxidized to porphyrins by other cellular processes. Some porphyrins, in turn, are excreted in urine and feces. Inhibition of an enzyme for heme biosynthesis can result in the inappropriate accumulation of that enzyme"s substrate. The more severe the enzyme"s inhibition, the greater the tissue accumulation of porphyrins, sometimes becoming severe enough to cause clinical porphyria. The reader is encouraged to consult any standard medical textbook for a detailed description of classical inherited forms of porphyria.

Figure 2:The Heme Biosynthetic Pathway

The enzymes that drive the heme biosynthetic pathway are: (1) d-aminolevulinate (ALA) synthetase, (2) ALA dehydratase, (3) uroporphyrinogen I synthetase (PBG deaminase) and uroporphyrinogen III cosynthetase, two enzymes that work in concert, (4) uroporphyrinogen decarboxylase, (5) coproporphyrinogen oxidase, (6) protoporphyrinogen oxidase, and (7) ferrochelatase (heme synthetase). Spilled porphyrins derived from porphyrinogens with 8, 7, 6, 5, and 4-carboxyl groups are largely excreted in the urine while the less polar 2-carboxyporphyrin (protoporphyrin) is excreted exclusively in the feces. The physiologically relevant pathway leading to heme is that leading via uroporphyrinogen III, in which the propionyl and acetyl groups are "reversed" compared to those of the type I pathway, which "dead ends" with coprophyrinogen I. The physiological significance of the type I pathway remains unclear; however, coproporphyrin I is elevated in hepatobiliary diseases and arsenic toxicity.