Comparison of Pyrazinamide with Isoniazid for Their Effects on the Heme Biosynthetic Pathway in Mouse Liver

Background/Objectives: Isoniazid (INH) and pyrazinamide (PZA) are first-line drugs used to treat tuberculosis (TB), but their use is generally contraindicated in patients with porphyria, a group of metabolic disorders caused by defects in the heme biosynthetic pathway. To investigate the basis for these contraindications, we compared the effects of INH and PZA on the heme biosynthetic pathway in mouse liver. Method: We investigated the hepatic expression and activity of the key enzymes involved in the heme biosynthetic pathway, including aminolevulinic acid synthase 1 (Alas1) and ferrochelatase (Fech). Additionally, we employed a metabolomic approach to analyze liver and fecal samples from the mice treated with INH or PZA. Result: We found that INH, but not PZA, significantly upregulated the expression and activity of Alas1, the rate-limiting enzyme in heme biosynthesis, while concurrently downregulating Fech, which converts protoporphyrin IX (PPIX) to heme. These changes resulted in the accumulation of the toxic intermediate aminolevulinic acid (ALA) and PPIX in the liver of INH-treated mice. In contrast, PZA had no measurable effect on the expression or function of Alas1 or Fech. Conclusions: These findings provide mechanistic insight into INH-induced porphyria exacerbation and suggest that PZA may not carry the same risk, challenging its current contraindication.