From the Guidelines
Lead and isoniazid both disrupt heme synthesis through different mechanisms, with lead inhibiting delta-aminolevulinic acid dehydratase (ALAD) and ferrochelatase, and isoniazid inhibiting delta-aminolevulinic acid synthase (ALAS) by depleting vitamin B6 (pyridoxine) 1.
Mechanisms of Disruption
- Lead inhibits several enzymes in the heme biosynthetic pathway, primarily delta-aminolevulinic acid dehydratase (ALAD) and ferrochelatase, causing accumulation of aminolevulinic acid (ALA) in blood and urine, and increased zinc protoporphyrin levels.
- Isoniazid, a tuberculosis medication, inhibits delta-aminolevulinic acid synthase (ALAS), the first and rate-limiting enzyme in heme synthesis, by depleting vitamin B6 (pyridoxine) 1.
Detection and Prevention
- These disruptions manifest as microcytic anemia and can be detected through elevated blood lead levels, increased free erythrocyte protoporphyrin, and elevated urinary ALA and coproporphyrin.
- Supplementation with pyridoxine (25-50 mg daily) is recommended during isoniazid therapy to prevent these effects and associated neurological complications 1.
Clinical Implications
- The risk for isoniazid-related hepatitis is minimal in infants, children, and adolescents, who generally tolerate the drug better than adults 1.
- Routine monitoring of serum liver enzyme concentrations is not necessary but should be considered in children at risk for hepatic disease 1.
From the Research
Effect of Lead on Heme Synthesis
- Lead intoxication results in a disturbance of heme biosynthesis, with the degree of disturbance depending on the severity and duration of exposure to lead 2.
- The prime targets of lead toxicity are the heme synthesis enzymes, including delta-aminolevulinate dehydratase, coproporphyrin oxidase, and ferrochelatase 3.
- Lead exposure can lead to increased excretion of delta-aminolevulinic acid and coproporphyrin III in the urine, as well as increased erythrocyte protoporphyrin levels 2.
Enzyme-Specific Effects
- Delta-aminolevulinate dehydratase activity is reduced in individuals exposed to lead, with the ALAD2 allele being more susceptible to lead inhibition than the ALAD1 allele 4, 5.
- Coproporphyrin oxidase and ferrochelatase activities are also reduced in individuals exposed to lead 2.
- Delta-aminolevulinate synthetase activity is increased in individuals exposed to lead 2.
Protection Against Lead-Induced Toxicity
- Vitamin C supplementation has been shown to restore lead-induced alterations in heme synthesis and drug metabolism in rats 6.
- Vitamin C supplementation can also reduce blood and liver lead concentrations, although the effect on renal lead contents is minimal 6.
Isoniazid Effects
- There is no direct evidence in the provided studies on the effects of isoniazid on heme synthesis.