The biochemical pathways of heavy metal poisoning are routes by which the metals pass in the body as they impair and destroy normal cellular and organ activity. The most common types of heavy metal poisoning are caused by lead, arsenic, cadmium and mercury. They are also the most extensively studied at the moment. Lead poisoning occurs mainly by the inhibitory effect that the metal imposes on enzymes and subsequent distortion of essential biochemical pathways. The metal disrupts calcium metabolism and subsequently causes neurotoxicity. It also inhibits reduction of the glutathione in the biochemical process meant to produce antioxidants. Lead also intrudes and redirects the heme synthesis pathway leading to the build up of aminolevulinic acid (ALA) in the cell. This results in the production of Reactive Oxygen Species (ROS) that mediate cell injury. Arsenic poisoning leads to the impairment of intracellular and intercellular communication pathways. Its effect on the signal transduction leads to the build up of free radicals that mediate cell death or injury. Mercury poisoning results from methylmercury. It has inhibitory effects that resemble those of the lead and uniquely induces the release of free radicals in cells.

Cadmium mainly poisons the cell by displacing essential nutrients such as calcium, zinc, iron and copper from biomolecules. The displaced metals precipitate in body fluids and tissues and may be excreted or accumulated in the body. Biochemical pathways by which metal poisoning occurs mainly involve inhibition of biosynthetic, regulatory and other forms of enzyme activities, altered signal transduction pathways, induction of the production of free radicals and displacement of biochemical reactions.

Biochemical Pathways of Heavy Metals Poisoning

Heavy metal poisoning is one of the most devastating health hazards that stem from environmental pollution. Industrial, agricultural and medical procedures contribute to the increase in exposure of people to heavy metals. Their poisoning impairs body systems like the renal system and central nervous system which often fail as a result of inhibition of the essential enzymes’ activity, disruption of the cell membrane’s integrity or interference of protein synthesis by the metals. The metals and their derivatives also cause toxicology by disrupting transcription and translation of genetic information, as well as the inhibition of neurological processes through blocking of neurotransmitters.

Heavy metals interfere with biochemical pathways by intruding the chemical structure of protein substrates, enzymes and some other influential reactants.

The above intramolecular reaction interferes with the reactivity of the thiol group and also occurs in enzymes as well as within individual aminoacids. They also bind to active sites of enzymes

They alter or halt these pathways through their intramolecular and intermolecular intrusion in reactants and enzymes (Ogwuegbu MO & Ijioma MA, 2003).

Biochemical Pathways of Lead Poisoning

Disruption of Calcium Metabolism and Neurotoxicity

Lead can activate calmodulin and displace calcium. Therefore, lead can interfere with calmodulin found on the surface of synaptic vesicles hence affecting protein phosphorylation and consequently impairing neurological behavior. This interferes with the roles of calcium in:

  • Releasing neurotransmitters,
  • Regulating certain enzymes that limit the rate at which neurotransmitters are synthesized,
  • The packaging of transmitters within vesicles of presynaptic compartments
  • Regulation of hormone-dependent cyclases

Enzyme Inhibition in Glutathione Metabolism Pathway

Lead can be bound to the sulfhydryl groups found in some enzymes.

Normal and functional glutathione derives its antioxidant properties from the thiol group that occurs in the cystein within it. This group can be readily reduced or oxidized.

Lead (like arsenic and mercury) interferes with glutathione metabolism by binding to its sulfhydryl complex of the key enzyme involved in this biochemical pathway. The enzyme is known as Glutathione reductase. It catalyzes reconversion of the glutathione disulfide (GSSG) to its initially reduced form (GSH).

This inhibition leads to the release of glutathione from cells such as lymphocytes into blood and subsequent elevation of its concentration in the bloodstream.

Lead Inhibitory Effect on the Heme Synthesis Pathway

Lead impairs the functioning of Delta-aminolevulinic acid dehydrogenase (ALAD) in the same manner as it does to Glutathione Reductase. This disrupts the Heme pathway by redirecting it in a manner that makes the cell to initiate a feedback mechanism. Products of these feedback reactions lead to the onset of free radical formation.

Free radicals formed in the cell may stem from peroxidation of lipids, reaction of sulphur oxides and hydrogen peroxide. They may damage the cell or induce signals which direct the cell to destroy itself. The diagram below illustrates the lead inhibition on the heme pathway

Ferrochelatase is another enzyme that is involved in the last step of heme synthesis and is also inhibited by lead. The cell attempts to implement a feedback mechanism whereby low levels of porphobilinogen activate ALA synthetase to catalyze the formation of ALA. The subsequent build up of this substance induce the formation of Reactive Oxygen Species (ROS) meant to execute the death of the cell.

Biochemical Pathways of Arsenic Poisoning

Arsenic metal poisoning is marked mainly by onset of the oxidative stress within the cell, disruption of its gene regulation processes, and improper methylation of DNA. These events lead to interference with activity of the tumor suppressor protein p53 and impairment of mechanisms of DNA repair and eventual apoptosis. Cell injury may also result from some effects of oxidative stress.  

Arsenic toxicity mainly lies in its reactivity with thiols, for example sulfhydryls found in transcription factors, cell cycle control and DNA repair proteins to which Zinc is also bound (Kitchin & Wallace, 2008).

The metal also inhibits Nucleotide Excision Repair (NER) and Base Excision Repair (BER) which are mechanisms by which nuisance DNA that results from mutation is removed. This results in the occurrence of mutations that would have been removed under normal circumstances.

Arsenic Poisoning on Signal Transduction Pathways

Arsenic has the capacity to trigger the release of Reactive Oxygen Species leading to the oxidative stress within the cell (Swaran J.S. Flora & Vidhu Pachauri, 2010). These ROS include a superoxide radical ion, nitric oxide and hydrogen peroxide which activate various cell-death signal pathways. It also induces the generation of dimethylarsinic peroxyl and dimethylarsinic species. This is seen in the diagram below, whereby:

As 3+ = Arsenic (III), MMA = Monomethyl Arsinic, PTPs = Permeability Transition Pores, PTKs =, MAPK =, AP-1 =, NOS = Nitric Oxides, ROS = Reactive Oxygen Species, Cdc42 =, NADPH ox =, Keap1 = Kelch – like ECH associated protein 1, Nrf2 = Nuclear factor-erythroid 2-related factor 2

The radicals are generated in intermediate steps above mediate cell injury but in other instances they also play critical roles in facilitating certain cell signal cycles that are essential for normal functioning and in moderating the transcription factor.

Arsenic Poisoning on Pyruvate Metabolism Pathway

Pyruvate Dehydrogenase (PDH) is an essential enzyme in cellular respiration. It catalyzes the oxidization of pyruvate to form acetyl CoA which is a molecule that forms an essential initial reactant of the TCA cycle. The enzyme is inhibited by arsenic when the metal binds to the thiol groups on its dihydrolipoate portion. This bars the enzyme from getting oxidated and thus rendering it inactive. The resultant effects include diminished ATP production and halting of glucogenesis.

Other enzymes of the TCA cycle that are blocked by arsenic include isocitratric acid dehydrogenase, alpha-ketoglutaric acid dehydrogenase, succinic acid dehydrogenase, NAD dehydrogenase and cytochrome C oxidase.

Mercury Poisoning

The reactive forms of mercury occur in two oxidation states, these are mercuric (+2) and mercurous (+1). Mercuric usually reacts with methyl groups in organic substances to form methylmercury (CH3Hg+) which is the source of most mercury poisonings. The reaction occurs in microbes that methylate inorganic mercury in the environment.

Human beings get poisoned by drinking water or taking food that contain methylmercury residues. Once in the body, it may enter cells, causing toxicity by inducing oxidative stress in the cell through free radicals which it forms from various biochemical reactions. The radicals include lipid peroxides, superoxide and hydrogen peroxide.

The metal also has inhibitory effects on various biosynthetic pathways, such as glutathione reduction reactions. This leads to depletion of GSH which is an essential antioxidant in cells.

Oxidative stress may be considered as one of the prime contributing mechanism in metal toxicity and thus provide a strong rationale for including antioxidants during chelation therapy.


Heavy metal poisoning therefore diverts essential biochemical pathways and results in formation of undesired compounds in cells. The compounds formed cause the onset of cell-destruction events and inhibit normal cell pathways. The redirection of cell-signaling pathways plays a major role in the toxicity of heavy metals. This results from the alteration of genetic information and subsequent impairment of DNA regulatory and control mechanisms over the affected biochemical pathways.

Heavy metal poisoning can be treated using chelating agents. They bear a significant clinical importance since they serve as antidotes for nearly all levels of heavy metal toxicity. These substances link metal ions to generate compounds that our bodies can get rid of without any difficulty. An example of a chelating agent is 2, 3-dimercaprol that is commonly used as a remedy for arsenic and lead toxicity. Another one is Meso 2, 3, -dimercaptosuccinic acid that does not only possess the potential to treat metal poisoning in people but also works in animals. Its main demerit is lipophobism that bars it from chelating metals that lie inside cells, since it cannot interact with the cell membrane lipoproteins for easy entry into the cell. The emerging practice in clinical heavy-metal detoxification involves combining of a chelating agent and an antioxidant. This serves to extract and detoxify intracellular metals and thus bears a substantial value for treatment of most forms of heavy metal poisoning.

A good chelating agent should have the following qualities:

  • Be able to extract the poisonous metal quickly from the body;
  • Have a strong binding ability and be nonpoisonous;
  • Be able to dissolve readily in the body fluids through which it is delivered at its site of action;
  • It should also permeate the cell and bind strongly to its target.