Pyrazinamide

Limits on what this shows

• Null findings: No pyrazinamide-alone effect on HO-1 in LO2 cells [37]. No pyrazinamide-alone data for ROS, membrane potential or ATP were reported in the LO2 study [37].
• At-risk subgroups: Not defined. Pre-existing liver disease and alcohol use raise hepatic risk per the label [1], which is a toxicity statement.

Direction

Drug-induced mitochondrial toxicity in vitro. A drug-toxicity finding, never a nutrient deficiency (Hard Rule 2).

Regulatory status

The labels make no mitochondrial statement; hepatic reaction is the principal adverse effect and is dose related [1][2].

Population evidence

No human mitochondrial or respiratory measurement was retrieved. A 1985 ultrastructural study of pyrazinamide and the liver in tuberculosis patients exists but has no abstract in the record [38]; only its title is known, so nothing is relied on. Tier B: Elmorsy 2016 [36], HepG2 cells exposed to rifampicin, isoniazid and pyrazinamide alone and in combination: approximate 24-hour IC50 0.5 mM, 70 mM and 84 mM; at 24 hours membrane potential fell (P=0.0005), complex I (P=0.0001) and complex III (P=0.0003) activity fell, NAD+ fell (P=0.0057), lactate rose (P<0.0001), combinations inhibited complex I synergistically, with mitophagy on electron microscopy; the page does not break results out per drug. Goh 2020 [37]: LO2 hepatocytes, pyrazinamide viability IC50 60 mM; membrane potential loss (P<0.0001) and caspase-3 rise were shown only for isoniazid 40 mM plus pyrazinamide 10 mM, and pyrazinamide alone did not suppress HO-1 where isoniazid did. Zhang 2016 [39]: zebrafish larvae at 1 to 5 mM pyrazinamide developed dose-dependent liver injury with apoptosis. For scale, plasma concentrations of 3 to 50 ug/mL [5] equal about 0.02 to 0.4 mM (pyrazinamide molar mass about 123 g/mol, my arithmetic), so the HepG2 IC50 is about 200 times the highest quoted plasma level.

Mechanism

Present in vitro only: impaired respiratory-chain complexes, membrane potential loss and mitophagy in hepatoma cells exposed to the drug set [36]. A narrative review states reactive intermediates and, for isoniazid plus rifampicin, membrane potential loss and cytochrome c release; it gives no pyrazinamide-specific mechanism [40]. The proposed disruption of membrane energetics by pyrazinoic acid was a hypothesis for the bacillus and is described in a Tier D page as discounted [45]; it is not human evidence.

Counter-evidence held on record

Counter-evidence and confounding The concentrations are far above plasma levels, the mitochondrial results are pooled across drugs, and hepatotoxicity in patients is also contributed by isoniazid and rifampicin. A pyrazinamide-alone human mitochondrial measurement is absent. Framing caution In vitro toxicity signal for database curation. It does not indicate a nutrient to replace and must not be turned into a mitochondrial-support or antioxidant recommendation.

Limits on what this shows

• Null and contradicting findings: MDA and nitrite no longer differed from controls after 2 months in the regimen cohort [43], and antioxidant enzymes recovered by 6 months in another [21]. Both abstracts leave the regimen contribution of pyrazinamide unseparated from the disease effect.
• At-risk subgroups: Elderly patients had higher allantoin than young patients on the regimen [42].

Direction

Mixed. Increased oxidative burden in animal and in vitro work and in one human drug-set cohort; reverse (improving) in disease-recovery cohorts; the metabolite pyrazinoic acid lowered oxidative stress in a rat model. Not a nutrient deficiency.

Regulatory status

Not discussed in the labels read [1][2].

Population evidence, human (combination-cohort label)

Walubo 1995 [42]: 10 young and 9 elderly patients on isoniazid, rifampicin and pyrazinamide; allantoin was similar to volunteers before treatment and the combination raised it in both groups, more in the elderly (P<0.05); the record gives day-1, day-30 and day-90 means of 8.22, 5.85 and 4.84 ug/mL (elderly) versus 1.89, 0.87 and 0.52 ug/mL (young) but the pairing is unclear. Lamsal 2007 [43]: 56 cases versus 50 controls; MDA 8.10 versus 3.45 nmol/mL (P<0.0001), vitamins C and E lower; in 35 followed for 2 months on a regimen including pyrazinamide 25 mg/kg/day, MDA fell to 3.84 nmol/mL and vitamin C rose (both P<0.0001), vitamin E unchanged, and vitamins C and E stayed below controls. Qi 2021 [21]: 86 patients versus 112 controls, MDA higher and GSH, SOD and catalase lower at baseline, recovering to the normal range over 6 months (regimen not stated, Tier C).

Population evidence, animal and cell (Tier B)

Adebayo 2018 [41]: rats given pyrazinamide 15 mg/kg three times a week for 8 weeks (7 per arm, alongside isoniazid, rifampicin and ethambutol arms) showed raised ovarian and uterine MDA and lower GST, GPx, SOD and catalase in the drug-treated groups; the abstract does not break this out per drug. Zhang 2016 [39]: zebrafish larvae at 1 to 5 mM had oxidative stress with liver injury. Goh 2020 [37]: the ROS rise was shown only for the isoniazid plus pyrazinamide combination.

Reverse-direction finding

Sahdev 2017 [44]: the metabolite pyrazinoic acid, 10 and 25 mg/kg daily for 15 days, restored oxidative stress parameters toward normal in rats with chemically induced colon carcinoma. A metabolite in a cancer model; not established for humans taking pyrazinamide.

Mechanism

Present in vitro and in animals as reactive-intermediate and mitochondrial stress [40][36]; absent as a human-measured effect of pyrazinamide alone.

Counter-evidence held on record

Counter-evidence and confounding Active tuberculosis lowers antioxidant capacity and raises MDA, so recovery with treatment masks any drug effect, and all human cohorts combine three or four drugs. Animal exposures are high relative to patients. Framing caution Do not translate into an antioxidant supplement recommendation. No pyrazinamide-specific source supports antioxidant supplementation.

Limits on what this shows

• Null and contradicting findings: Sharp 1990 [17]: a second patient on a four-drug regimen with isoniazid and pyrazinamide recovered once isoniazid was withdrawn, so attribution in standard regimens is uncertain. Tuberculosis itself lowers iron: in 33 patients (regimen not named) serum iron was subnormal in 66 percent and marrow iron absent in 34 percent before treatment, and serum iron and hemoglobin rose on treatment [19]; in 75 men iron was lower than in healthy subjects and did not change over 60 days [20].
• At-risk subgroups: Not defined. The one detailed case had a hemoglobinopathy trait [13].

Direction

Utilization block with iron retained or raised (label: "increased serum iron concentration"), not iron depletion. Anemia is an outcome and is not iron deficiency (Hard Rule 2). Supplemental iron would not be the remedy.

Regulatory status

Both labels read list "thrombocytopenia and sideroblastic anemia with erythroid hyperplasia" as rare reactions, with increased serum iron concentration and rare effects on clotting; no frequency is given [1][2].

Population evidence

Case level (Tier B). Colucci 2012 [13]: 54-year-old woman with heterozygous alpha-thalassemia, ring sideroblasts and dyserythropoiesis, attributed to pyrazinamide; hemoglobin normalized in about 3 months after the drug was stopped and pyridoxine given. Three older reports exist whose abstracts were unavailable: McCurdy 1966 (title "Reversible sideroblastic anemia caused by pyrazinoic acid") [15], MacCurdy and Simon 1970 (thrombocytopenia and sideroblastic anemia, regimen indexed with isoniazid, para-aminosalicylic acid, cycloserine and streptomycin) [16], and a 2012 correspondence [14]; no result from them is relied on. No cohort measuring ferritin, transferrin saturation or marrow iron on a pyrazinamide-containing regimen with incidence was retrieved.

Mechanism

Postulated, not established in the abstracts read: impaired heme synthesis with mitochondrial iron accumulation. A 1980 review indexes pyrazinamide among drugs linked to mitochondrial damage and sideroblastic change but its abstract was not available [18].

Counter-evidence held on record

Counter-evidence and confounding Disease-related low iron and inflammation are the main confounders, and the label gives no frequency. Why not orange: the label statement is an adverse-reaction line for a rare event, not a measured iron deficit, and the supporting cases are Tier B. Framing caution Do not read as iron deficiency or as a reason to take iron. The event described is a rare utilization block that reversed when the drug was stopped.

Limits on what this shows

• Null findings: No significant on-treatment change in copper in de Moraes [20].
• At-risk subgroups: Not defined.

Direction

Neutral for the drug; disease-linked and conflicting. One cohort found copper low and rising on treatment (reverse direction), the other found copper high and unchanged. No depletion or excess is attributable to pyrazinamide.

Class extrapolation

CLASS EXTRAPOLATION (Tier C, capped at yellow). Pyrazinamide was NOT confirmed in either cohort: the regimen is not stated in either abstract read [21][20]. A third trace-element cohort listing copper had no abstract available [22].

Regulatory status

Copper is not mentioned in the pyrazinamide labels [1][2].

Population evidence

Qi 2021 [21]: 86 patients versus 112 controls; zinc, selenium and copper significantly lower in tuberculosis, rising over 6 months of treatment. de Moraes 2014 [20]: 75 men; copper and copper/zinc ratio higher than in healthy subjects, no significant change in iron, zinc or copper/zinc at 30 or 60 days; lower copper associated with sputum negativity at 30 but not 60 days. PubMed listing "pyrazinamide copper" returned 10 records, none a human copper measurement on pyrazinamide (hits were metal-complex chemistry, a computational PncA-metal paper and the de Moraes cohort).

Mechanism

Absent. No copper chelation, absorption or transport mechanism for pyrazinamide is described in the label or retrieved sources. Pyrazine carboxamide metal-complex chemistry papers appeared in the PubMed listing but were not opened and are not human physiology.

Counter-evidence held on record

Counter-evidence and confounding Copper rises with inflammation (an acute-phase effect), which probably explains the high baseline in one cohort; the conflicting directions across the two cohorts show disease and inflammation, not a drug, set the signal. Framing caution Context flag only. It is not a copper-depletion or copper-excess claim for pyrazinamide and carries no supplement or avoidance recommendation.

Limits on what this shows

• Null and contradicting findings: Shannon diversity was preserved on treatment [31]; untreated TB itself lowers diversity [32]; mouse dysbiosis from conventional TB chemotherapy did not reduce drug exposure [35]. Metagenomic pathways for vitamin biosynthesis were increased, not decreased, in the treated Haitian patients [31]. No functional or nutrient consequence (vitamin K, B vitamins, short-chain fatty acids) was measured for pyrazinamide.
• At-risk subgroups: Not defined.

Direction

Composition change (risk), not a nutrient deficiency. In one cohort the direction was microbiota affecting drug exposure, not the drug affecting microbiota [34].

Regulatory status

No microbiome statement in the labels read [1][2]. The label records gastrointestinal disturbance (nausea, vomiting, anorexia) [1].

Population evidence (combination-cohort label)

Wipperman 2017 [31]: Haiti, HIV-negative; 19 patients on isoniazid, rifampin, pyrazinamide and ethambutol (mean 3.4 months) versus 50 uninfected and 25 latent-infection controls; Shannon diversity did not differ, observed OTUs were lower (P=0.0074 and P=0.0122), treatment drove composition (PERMANOVA P=0.023), with large falls in Lactobacillus, Coprococcus, Ruminococcus, Bifidobacterium and Blautia; 19 cured patients still differed from controls a mean 1.2 years later (P=0.007) though Shannon was modestly higher (P=0.0487). Meng 2022 [32]: China; untreated TB n=41 had lower diversity than latent infection n=30 or healthy volunteers n=49; 2-month HRZE n=28 and 6-month n=20 groups showed higher evenness and Simpson diversity than untreated TB (PCoA P=0.022 for the 6-month group), Clostridium falling and Veillonellaceae and Bacteroidaceae rising. Zhu 2025 [34]: 99 and 32 patients on the four drugs; higher pre-treatment diversity was associated with higher drug exposure (opposite direction).

Tier B, pyrazinamide given alone

Namasivayam 2017 [33]: isoniazid, rifampin and pyrazinamide each given singly to mice (n=4 uninfected for pyrazinamide); "RIF but not INH or PZA caused a decrease in bacterial diversity"; pyrazinamide alone produced compositional alterations including genus Anaeroplasma and some Clostridia, and only minor changes in infected mice; the full three-drug regimen left a dysbiosis lasting at least 3 months. No recovery data for single drugs.

Mechanism

Not established. Pyrazinamide is described as a prodrug activated by a mycobacterial enzyme (Tier D page [45]), it is well absorbed and about 70 percent is excreted in urine [1], and no retrieved study tested whether pyrazinamide or pyrazinoic acid reaches or acts on gut bacteria. The murine compositional changes show an effect exists but not its pathway.

Counter-evidence held on record

Counter-evidence and confounding Disease-driven dysbiosis, cross-sectional designs, small samples and the rifampin component (the mouse data name rifampin as the diversity driver) confound every human cohort. Why not orange: no pyrazinamide-containing versus pyrazinamide-free human comparison exists in the retrieved record, and the only single-drug arm is murine. Framing caution This is a signal of microbial composition change on a multi-drug regimen. It is not evidence of vitamin or short-chain fatty acid deficiency, and not a reason to add probiotics or supplements.

Limits on what this shows

• Null findings: A PubMed listing for pyrazinamide with anemia, hemolysis or methemoglobinemia returned the two sideroblastic reports and otherwise unrelated methemoglobinemia literature; no pyrazinamide hemolysis or methemoglobinemia record appeared in the 37 shown.
• At-risk subgroups: Not defined.

Direction

Reduced oxygen-carrying capacity through a rare anemia outcome. Not a nutrient deficiency and not the drug's intended action (Hard Rule 2).

Regulatory status

Labels list rare thrombocytopenia and sideroblastic anemia with erythroid hyperplasia and increased serum iron [1][2]. They do not list hemolytic anemia or methemoglobinemia in the text read.

Population evidence

Case level only (Tier B): normalization of hemoglobin within about 3 months after stopping pyrazinamide in one case [13]; older case reports not retrievable [15][16][14]. No incidence cohort was retrieved. In a cohort with regimen unnamed, hemoglobin rose over 3 months of chemotherapy though 7 initially anemic patients stayed anemic [19].

Mechanism

Heme-synthesis block (see Iron). No hemolytic or methemoglobin-forming mechanism was found for pyrazinamide.

Counter-evidence held on record

Counter-evidence and confounding Anemia in tuberculosis has many causes (inflammation, iron and folate deficiency, other regimen drugs) and the only quantified cohort improved with treatment [19]. The same case evidence as the Iron entry; counted once (Overlap map). Framing caution This is an adverse-event outcome, not a deficiency. Do not use it to imply a need for iron or any nutrient.

Limits on what this shows

• Null findings: Goh 2020 reported no pyrazinamide-alone ATP data and none for ATP at all in the text read [37].
• At-risk subgroups: Not defined.

Direction

Drug-induced reduction of cellular energy output in vitro. Not a nutrient deficiency (Hard Rule 2).

Regulatory status

Not discussed in the labels read [1][2].

Population evidence

No human data. Elmorsy 2016 [36]: ATP declined dose- and exposure-time-dependently (4, 24 and 48 hours) alongside lower membrane potential, lower complex I and III activity, lower NAD+ and higher lactate; the page does not give per-drug ATP results and states only the 24-hour IC50 of 84 mM for pyrazinamide.

Mechanism

Present in vitro: respiratory-chain impairment with a shift toward lactate [36].

Counter-evidence held on record

Counter-evidence and confounding Same underlying source as the Mitochondrial burden entry, which this entry does not independently confirm (Overlap map). Concentrations are far above plasma levels. Framing caution Do not read as an energy-metabolism or fatigue claim and do not use to suggest any nutrient.