Zileuton

Limits on what this shows

• Null findings: Mitochondrial membrane potential unchanged in the stellate cell study [17]. In the mouse study, resistant animals had no adverse liver pathology [7].
• At-risk subgroups: Patients with ALT elevation; women aged 65 and over had the highest ALT elevation rate in the 12-month cohort (10.1%) [6]. Whether this reflects mitochondrial vulnerability is not tested.

Direction

Possible mitochondrial stress in the drug-toxicity model (excess burden, not a deficiency). Context: a hepatotoxicity mechanism.

Regulatory status

Labels do not mention mitochondrial effects [1][2][3]. The labels do document hepatocellular ALT elevation [1][2].

Population evidence

No human mitochondrial data. Mouse [7]: transcriptome analysis of female Diversity Outbred mice dosed for 7 days implicated mitochondrial dysfunction and altered fatty-acid oxidation, with microvesicular fatty change, hepatocyte mitosis and necrosis in susceptible animals (abstract and record summary). Cell [17]: in rat pancreatic stellate cells, zileuton decreased mitochondrial resazurin reduction, interpreted by the authors as slowed Krebs cycle flow; mitochondrial membrane potential showed no detectable change (abstract only, concentrations not stated). Human context: ALT of 3 times the upper limit or more in 4.4% of 2,458 treated patients versus 1.0% of usual-care patients, predominantly hepatocellular, no jaundice or liver failure [6]. The human data show liver injury, not mitochondrial injury.

Mechanism

Named but unmeasured in humans: mitochondrial dysfunction and fatty-acid oxidation changes in susceptible mouse livers [7].

Counter-evidence held on record

Counter-evidence and confounding The mouse result is a 7-day high-diversity model of rare idiosyncratic injury; human cases are uncommon and mostly resolved on stopping (mean time to resolution 4 weeks) [6]. The stellate cell study used a non-hepatic cell type with unspecified concentrations. Framing caution This is a drug-toxicity mechanism signal from animal and cell work, not a nutrient deficiency. Do not recommend mitochondrial supplements (for example coenzyme Q10 or carnitine) from this entry.

Limits on what this shows

• Null findings: Zileuton did not restore glutathione depletion in glutamate-stressed HT22 cells [16]. The stellate cell paper does not clearly state whether zileuton reversed the reduced-to-oxidized glutathione ratio [17]. Two further records, a 2012 study of the antioxidative properties of lipoxygenase inhibitors that lists zileuton among its keywords [19] and a 2025 paper on zileuton and vancomycin nephrotoxicity [18], had no abstract in the records retrieved and were not opened, so they are not used.
• At-risk subgroups: In the label and the 12-month cohort, ALT elevation of 8 times the upper limit or more was more frequent in women (1.8% versus 0.5% in men), and ALT elevation was 10.1% in women aged 65 and over versus 4.1% under 65 [6]. This describes liver injury, not oxidative stress.

Direction

Mixed. Excess nitrosative stress in the toxicity model (a drug-toxicity mechanism, not a nutrient deficiency); reverse (protective) in injury models. Neither direction is a depletion of an antioxidant nutrient.

Regulatory status

Labels do not mention oxidative stress, antioxidants or glutathione [1][2][3].

Population evidence

No human data. Toxicity model [7]: female Diversity Outbred mice given zileuton daily by oral gavage for 7 days (dose not given in the abstract record); serum liver enzymes rose with wide individual variability; susceptible livers showed higher inducible nitric oxide synthase and nitrotyrosine; transcriptome pointed to altered glutathione detoxification among other pathways. Protective models: melatonin plus zileuton (20 mg/kg each) in kidney-fibrosis mice and RSL3-treated kidney cells lowered 4-HNE and raised GPX4 [13]; zileuton reduced erastin-induced lipid peroxidation in HT22 neuronal cells and spinal-cord-injured mice [14]; AgNPs plus zileuton lowered MDA and raised GPX4 activity in 75 female rats, but only the combination arm is reported in the abstract [15]; zileuton lowered glutamate-induced ROS in HT22 cells [16]; zileuton raised Nrf2 phosphorylation and antioxidant enzymes (catalase, GCL, HO-1, NQO1, SOD1, SOD2) in H2O2-stressed rat pancreatic stellate cells [17]. All of these were read as abstracts or through a summarizing tool; none gives a human effect size or confidence interval.

Mechanism

Named for the protective direction: 5-lipoxygenase inhibition and an Nrf2-linked antioxidant response [17]; the chemistry of the N-hydroxyurea group as a redox-active iron reductant at the enzyme [9]. Named for the toxic direction: nitrosative stress with iNOS and nitrotyrosine rise in susceptible livers [7].

Counter-evidence held on record

Counter-evidence and confounding Every protective result comes from an injury model in which an oxidative insult was applied first, often with a second agent in the treated arm, so the effect of zileuton alone on baseline redox status in healthy people is unknown. The nitrosative signal is from a genetically diverse mouse model of rare idiosyncratic liver injury and may not transfer to humans. Framing caution This is not a claim that zileuton depletes or boosts antioxidants. Do not recommend antioxidant or glutathione-precursor supplements from this entry. Liver injury on zileuton is managed by ALT monitoring per the label.

Limits on what this shows

• Null findings: No iron-lowering effect reported in any retrieved zileuton source. The sickle cell phase I abstract reports no clinically significant safety changes at doses up to 3,000 mg/day, without naming iron or ferritin [11].
• At-risk subgroups: None identified from zileuton data. Baseline iron deficiency in people with asthma, menstruating women and children is a population context, not a zileuton finding.

Direction

Neutral or unknown for body iron stores. The chelation described is of enzyme-bound iron in vitro; it is not evidence of systemic depletion or retention.

Regulatory status

No statement on iron, anemia or hemoglobin in the immediate-release label, the extended-release label or the 2012 FDA label text [1][2][3]. The extended-release label lists low white-cell count, not anemia, as the hematologic laboratory finding [2]. Table 2 of the immediate-release label (an image) could not be rendered by the fetch tool.

Population evidence

None in humans. A PubMed listing for zileuton with hemoglobin, anemia, methemoglobin or hemolysis returned 10 records, none an iron, hemoglobin or hemolysis report for zileuton [23]. Two drug-information pages (Tier D transcriptions of label data) list no anemia, hemoglobin or iron effect [21][22].

Mechanism

Present at the enzyme. Zileuton is an iron-ligand 5-lipoxygenase inhibitor [8]; its N-hydroxyurea moiety chelates the active ferric iron and reduces it to ferrous iron [9]. In cell and rodent ferroptosis models zileuton is protective: iron content was measured in spinal-cord-injured mice but the abstract gives no value [14]; Fe2+ was lower in the AgNPs plus zileuton arm than in diseased rats, with no zileuton-alone result reported in the abstract [15]. Peak plasma concentration at 2,400 mg/day (about 20 micromolar) is far above the literature enzyme IC50 (0.3 micromolar) [8], but 93% albumin binding [1] and the absence of any iron measurement leave the systemic consequence untested.

Counter-evidence held on record

Counter-evidence and confounding Hard Rule 2: anemia is not iron deficiency and a leukopenia finding is not an iron finding. The ferroptosis papers use iron content as a model endpoint after an insult, not as a nutrient-status measurement. Framing caution This is a mechanism note. It does not show that zileuton lowers body iron, and no iron supplement is recommended. Excess iron has its own risks.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C source was found to support even a yellow grade, and no circulating consumer claim about zileuton and copper was found in the Tier D pages that could be reached (Drugs.com, RxList, Wikipedia). This is a disclosed gap, not a finding of safety. Kept independent of Iron (Hard Rule 7).

What was searched

PubMed listing for zileuton AND (copper OR ceruloplasmin OR zinc OR selenium OR vitamin): 11 records, first 10 read, none concerning zileuton and copper (results were a selenium carbon-dot nanoplatform, a homocysteine-5-lipoxygenase paper, a tilapia study, a tuberculosis repurposing paper, a granuloma annulare case treated with a 5-lipoxygenase inhibitor and vitamin E, and others). US labels [1][2][3] and two Tier D pages [21][22] contain no copper statement. 5-lipoxygenase is an iron enzyme, so the drug's enzyme chemistry gives no copper hook. Earlier web searches (before the shared budget ran out) were aimed at iron redox, hemoglobin and ferroptosis, not copper specifically. Repair pass 2026-10-08: Crossref title/abstract-word search "zileuton copper ceruloplasmin" returned 10 records, nine generic copper or ceruloplasmin papers (cervical carcinoma, dairy cows, Alzheimer disease and others) and one USP monograph entry for zileuton with no copper content [26]. PubMed listings for zileuton with copper, ceruloplasmin, serum copper or cuproptosis phrasings were requested four times and refused by the proxy (HTTP 429) each time, so no second PubMed copper result was obtained.

Channel outcomes

Opened: DailyMed Zyflo and extended-release labels, FDA 2012 label PDF, Drugs.com, RxList. PubMed listing: worked, one query on copper (page 2 of 11 results not read). Web search: budget exhausted, so copper-specific web phrasings (for example zileuton serum copper, ceruloplasmin) were not run. Crossref, Europe PMC and OpenAlex listings: rate-limited, not used for copper. Repair pass: Crossref worked for one phrasing; PubMed refused four further copper phrasings (429); the web-search budget remained exhausted, Europe PMC refused one request (429) and OpenAlex search-listing URLs returned fetch errors. Judgement: probable true gap with a persisting tooling caveat; one PubMed phrasing (11 records) and one Crossref phrasing were read in full.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C evidence that zileuton alters the gut microbiome, and no circulating consumer claim to rebut. The label's microflora statement is a pharmacokinetic fact about how the drug is metabolized, not evidence of microbiome risk. This is a disclosed gap, not a finding of safety.

What was searched

PubMed listings: zileuton AND (microbiome OR microbiota OR dysbiosis OR gut OR intestinal flora): 7 records, none a zileuton microbiome study (a 2025 Science mouse paper on leukotrienes and food-allergen absorption, a 2025 allergic rhinitis multi-omics paper, a rat colitis treatment study from 1996, and others); zileuton AND (C. difficile OR fecal microbiota OR 16S OR short-chain fatty acids OR bile acids): returned the PubMed home page instead of a results list (treated as unreadable, not as a zero); zileuton AND (dysbiosis OR fecal microbiota OR gut microbiome): zero results. One earlier web search (zileuton gut microbiota mice 16S sequencing) returned only generic mouse 16S method papers. Repair pass 2026-10-08: PubMed listing zileuton AND (microbiota OR microbiome OR 16S OR dysbiosis): 3 records, none a zileuton-on-microbiome study (a 2025 allergic rhinitis multi-omics paper that proposes zileuton as a docking candidate without testing it, a 2024 Nature Communications mouse paper that uses zileuton only as a 5-lipoxygenase blocking tool in an IgA study and reports no microbiota result for it, and a 2025 moxibustion rat paper that lists zileuton O-glucuronide among urinary metabolites) [25]. Crossref search zileuton with gut microbiome 16S sequencing returned 15 generic 16S papers, none naming zileuton (391,975 loosely matched records; the search ranks poorly for rare drug names) [26]. The Nature Communications record was also read as a single OpenAlex record (api.openalex.org/works/pmid:39256385) [25]. The extended-release label states the inactive N-dehydroxylated metabolite is formed by gastrointestinal microflora before absorption [2]; this is a microbiome-to-drug effect and does not show a drug-to-microbiome effect (Hard Rule 4).

Channel outcomes

PubMed listings: worked on three phrasings. Web search: one query ran before the budget was exhausted. Other databases: rate-limited. Repair pass: one further PubMed phrasing worked, one Crossref phrasing worked, one Europe PMC request refused (429), web search still exhausted. Judgement: probable true gap (PubMed zero or non-relevant results across four phrasings); the remaining uncertainty is tooling, since full-text microbiome mentions inside non-indexed papers could not be searched.

Limits on what this shows

• Null findings: Mitochondrial membrane potential unchanged [17]. A PubMed listing for zileuton with mitochondria, ATP or respiration returned 60 records (first page read); none was an ATP or respiration measurement for zileuton [23].
• At-risk subgroups: None identified.

Direction

Unknown. The surrogate in the cell study (reduced resazurin reduction) points toward lower metabolic activity; the membrane potential did not change.

Regulatory status

Labels do not mention energy metabolism [1][2][3].

Population evidence

No human data. Cell [17]: reduced mitochondrial resazurin reduction in stellate cells; the abstract reports no ATP or respiration measurement. Mouse [7]: fatty-acid oxidation changes by transcriptome. This entry sits at the floor of yellow because both findings are surrogates.

Mechanism

Plausible but unmeasured: slowed Krebs cycle flow [17] and changed fatty-acid oxidation [7] could lower cellular ATP output.

Counter-evidence held on record

Counter-evidence and confounding Shared origin with Mitochondrial burden: the same two papers [7][17] support both entries and must not be counted as independent confirmation (see Overlap map). Oxidative stress also shares [7] and [17]. Framing caution This is not a claim of low cellular energy. Do not recommend energy-support supplements from this entry.

Limits on what this shows

• Null findings: PubMed listing for zileuton with hemoglobin, anemia, methemoglobin or hemolysis: 10 records, none a zileuton hemolysis, methemoglobin or anemia report [23]. Fetal hemoglobin did not rise in the human phase I [11].
• At-risk subgroups: People with sickle cell disease are the only population studied with a hemoglobin-related endpoint; the trial was small and its design (dose escalation, safety) could not detect a modest hemoglobin change.

Direction

Reverse or neutral. There is no deficit or reduced oxygen-carrying signal. The yellow grade records the one Tier B hemoglobin-related finding and the null human data so the category is not left blank.

Regulatory status

Immediate-release label: no hemoglobin or anemia statement in the text retrieved; low white-cell count at or below 2.8 x 10^9/L in 1.0% of 1,678 zileuton patients versus 0.6% of 1,056 placebo patients [1]. Extended-release label: low white-cell count below 3.0 x 10^9/L in 2.6% versus 1.7% on placebo; no anemia or hemoglobin finding [2]. Two Tier D pages that reproduce label data list no anemia, hemoglobin, hemolysis or methemoglobin entry [21][22].

Population evidence

Cell [10]: K562 cells and erythroid progenitors from people with sickle cell anemia and from people with normal genotypes; zileuton increased gamma-globin expression and fetal hemoglobin synthesis dose-dependently through an L-arginine/nitric oxide/cGMP pathway (abstract; concentrations not stated). Human [11]: phase I dose-escalation, twice-daily zileuton for 6 weeks in sickle cell disease; 14 consented, 4 failed screening, 11 received drug, 2 withdrew after acute sickle events; 1,200 mg twice daily tolerated in 3 patients, then escalation to 3,000 mg per day with 1,800 mg alternating with 1,200 mg in 6 patients; no clinically significant safety changes; fetal hemoglobin did not increase (conference abstract via a summarizing fetch of an OpenAlex record; total hemoglobin and hemolysis markers not reported in the retrieved text). A narrative review repeats that the phase I trial was safe and tolerable [12].

Mechanism

In vitro only: nitric oxide/cGMP-mediated gamma-globin induction [10]. No mechanism for reduced oxygen delivery was identified. Methemoglobin and hemolysis, the oxygen-delivery risks of some N-hydroxyurea compounds, were searched for zileuton and not found (see Fails verification).

Counter-evidence held on record

Counter-evidence and confounding Hard Rule 2: fetal hemoglobin induction is an exploratory pharmacologic effect, not an oxygen-delivery benefit or deficit, and leukopenia is a white-cell outcome. Sickle cell disease itself drives hemoglobin and hemolysis changes (confounding by indication). Framing caution This entry does not say zileuton harms or improves oxygen delivery. It records that no hemoglobin, hemolysis or methemoglobin signal was found.