Tohoku J. Exp. Med., 2002, 196 (2)

Review

Lead, Chemical Porphyria, and Heme as a Biological Mediator

HIROYOSHI FUJITA, CHIAKI NISHITANI and KAZUHIRO OGAWA

Laboratory of Environmental Biology, Hokkaido University School of Medicine, Sapporo 060-8638

One of the most well-characterized symptoms of lead poisoning is porphyria. The biochemical signs of lead intoxication related to porphyria are d-aminolevulinic aciduria, coproporphyrinuria, and accumulation of free and zinc protoporphyrin in erythrocytes. From the 1970s to the early 80s, almost all of the enzymes in the heme pathway had been purified and characterized, and it was demonstrated that d-aminolevulinic aciduria is due to inhibition of d-aminolevulinate dehydratase by lead. Lead also inhibits purified ferrochelatase; however, the magnitude of inhibition was essentially nil even under pathological conditions. Further study proved the disturbance of iron-reducing activity by moderate lead exposure. Far different from these two enzymes, lead failed to inhibit purified coproporphyrinogen oxidase, i.e., the mechanism of coproporphyrinuria has not yet been understood. During the 80s to the 90s, the effects of environmental hazards including lead were elucidated through stress proteins, indicating the induction of some heme pathway enzymes as stress proteins. At that time, gene environment interaction was another focus of toxicology, since gene carriers of porphyrias are considered to be a high-risk group to chemical pollutants. Toxicological studies from the 70s to the 90s focused on the direct effect of hazards on biological molecules, such as the heme pathway enzymes, and many environmental pollutants were proved to affect cytosolic heme. Recently, we demonstrated the mechanism of the heme-controlled transcription system, which suggests that the indirect effects of environmental hazards are also important for elucidating toxicity, i.e., the hazards can affect cell functions through such biological mediators as regulatory heme. It is, therefore, probable that toxicology in the future will focus on biological systems such as gene regulation and signal transduction systems.

Keywords —— heme metabolism; lead; d-aminolevulinate dehydratase; d-aminolevulinate synthase; Bach1

© 2002 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2002, 196, 53-64

Address for reprints: Hiroyoshi Fujita, Department of Preventive Medicine, Hokkaido University School of Medicine, 7 Nishi, Kita 15-Jyo, Kita-ku, Sapporo 060-8638, Japan.

e-mail: alfujita@med.hokudai.ac.jp

This paper was presented at the Sendai Symposium: Paradigm Shift in Heavy Metal Toxicology held on November 21-22, 2001.