Tobacco Enhances Hepatotoxicity of Isoniazid in Tuberculosis: Mechanisms and Clinical Implications

Abstract

Tuberculosis (TB) remains a significant global health challenge, with isoniazid (INH) being a cornerstone of its treatment. However, INH-induced hepatotoxicity is a major concern, leading to treatment interruptions and poor outcomes. Emerging evidence suggests that tobacco use exacerbates INH-related liver damage. This review explores the mechanisms by which tobacco enhances INH hepatotoxicity, including oxidative stress, cytochrome P450 enzyme induction, and immune modulation. Clinical implications and strategies to mitigate this risk are also discussed.

Introduction

Tuberculosis (TB) is a leading infectious cause of mortality worldwide, with an estimated 10 million cases annually (WHO, 2023). Isoniazid (INH), a first-line anti-TB drug, is highly effective but associated with dose-dependent hepatotoxicity. Approximately 5–20% of patients experience elevated liver enzymes, and severe liver injury occurs in 1–3% (Tostmann et al., 2008).

Tobacco use, prevalent among TB patients, has been linked to increased drug toxicity. Cigarette smoke contains over 7,000 chemicals, many of which induce hepatic enzymes and promote oxidative stress (Talhout et al., 2011). This article examines how tobacco exacerbates INH-induced hepatotoxicity and proposes clinical interventions to reduce risk.

Mechanisms of INH-Induced Hepatotoxicity

INH hepatotoxicity results from multiple pathways:

1. Reactive Metabolite Formation

   • INH is metabolized by hepatic N-acetyltransferase 2 (NAT2) into acetylisoniazid, which is further hydrolyzed to acetylhydrazine and hydrazine.
   • These metabolites generate reactive oxygen species (ROS), leading to lipid peroxidation and mitochondrial dysfunction (Metushi et al., 2016).

2. Genetic Predisposition

   • Slow acetylators (NAT25/6/*7 alleles) have higher hepatotoxicity risk due to prolonged INH exposure (Cheng et al., 2017).

3. Immune-Mediated Injury

   
   • INH metabolites may act as haptens, triggering immune-mediated liver damage (Cho et al., 2020).

Tobacco’s Role in Exacerbating INH Hepatotoxicity

1. Induction of Cytochrome P450 Enzymes

• Tobacco smoke contains polycyclic aromatic hydrocarbons (PAHs), which upregulate CYP1A2 and CYP2E1 (Nebert et al., 2004).
• Increased CYP2E1 activity enhances INH bioactivation, generating more hepatotoxic metabolites (Wang et al., 2018).

2. Oxidative Stress Amplification

• Cigarette smoke depletes glutathione (GSH), a critical antioxidant (Yahya et al., 2019).
• INH further reduces GSH, worsening oxidative liver injury (Sodhi et al., 1997).

3. Pro-Inflammatory Effects

• Tobacco increases TNF-α and IL-6, promoting hepatic inflammation (Arnson et al., 2010).
• Combined with INH, this accelerates hepatocellular necrosis (Zhang et al., 2021).

4. Impaired Drug Clearance

• Smoking alters hepatic blood flow, potentially delaying INH elimination (Zevin & Benowitz, 1999).

Clinical Evidence

Several studies support tobacco’s hepatotoxic synergy with INH:

• A 2015 Indian study found smokers on INH had 3.2-fold higher ALT elevations than non-smokers (Sharma et al., 2015).
• A meta-analysis reported smokers had 1.8× increased risk of severe hepatotoxicity (Liu et al., 2020).

Management Strategies

To mitigate risk, clinicians should:

1. Screen for Smoking Status – Assess tobacco use before initiating INH.
2. Monitor Liver Enzymes Closely – Increase frequency in smokers.
3. Antioxidant Supplementation – N-acetylcysteine (NAC) may reduce oxidative damage (Bhattacharyya et al., 2019).
4. Smoking Cessation Programs – Integrate TB treatment with nicotine replacement therapy.

Conclusion

Tobacco exacerbates INH-induced hepatotoxicity through metabolic, oxidative, and inflammatory pathways. Recognizing this interaction is crucial for optimizing TB therapy. Future research should explore pharmacogenomic-guided dosing and targeted antioxidant therapies for high-risk patients.

References

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Tags: #Tuberculosis #Isoniazid #Hepatotoxicity #Tobacco #DrugMetabolism #OxidativeStress #CYP450 #PublicHealth