Smoking-induced liver injury and related diseases: Molecular mechanisms, pathogenic amplification, and clinical implications

Table 2 Major toxic constituents of tobacco smoke and their established mechanisms of hepatic injury

Toxic component	General pathogenic mechanism	Specific hepatotoxicity mechanism	Ref.
Polycyclic aromatic hydrocarbons	Aryl hydrocarbon receptor activation and systemic enzyme induction; and DNA adducts	CYP1A1/1B1 mediated epoxidation; DNA adducts: Form covalent bonds with hepatic DNA, initiating mutagenesis	[35-37]
Nitrosamines	DNA alkylation	CYP2E1 mediated α-hydroxylation; DNA alkylation: Potent alkylating agents covalently modify DNA, initiating mutagenesis	[38]
Acrolein	Protein adduction and oxidative damages	Glutathione depletion: An electrophile that rapidly depletes hepatic glutathione, impairing detoxification; mitochondrial toxicity: Disrupts mitochondrial function in hepatocytes	[39-41]
Benzene	Chromosome aberrations; oxidative stress and apoptosis; aberrant DNA repair mechanisms and epigenetic alterations	CYP2E1 mediated oxidation; cytotoxicity: Causes oxidative damage and necrosis in liver cells	[42-44]
Cadmium	Oxidative stress	Accumulation: Long-term accumulation in the liver (half-life: 25-30 years); inflammation: Inhibits antioxidant enzymes and induces chronic inflammation	[45]
Nicotine	Highly addictive	Lipid metabolism: Dysregulates hepatic lipid metabolism, promoting steatosis; fibrosis: Accelerates liver fibrogenesis via oxidative stress pathways	[46,47]
Free radicals	Macromolecule oxidation	Lipid peroxidation: Directly damages hepatocyte membranes via lipid peroxidation; Kupffer cell activation: Triggers immune response in the liver	[4,48]
Carbon monoxide	Competitive binding to hemoglobin	Hypoxia: Causes hypoxic injury to hepatocytes by reducing oxygen delivery	[49,50]

CYP2E1: Cytochrome P450 2E1.