Mitochondrial versus microsomal bioactivation of paracetamol by human liver and kidney tissues. (15th June 2022)

• Record Type: Journal Article
• Authors: Arzuk, Ege; Tokdemir, Mehmet; Orhan, Hilmi
• Is Part Of: Toxicology letters. Volume 363(2022)
• Page Start: 36
• Page End: 44
• Publication Date: 2022-06-15
• Subjects: Human -- Paracetamol -- Mitochondria -- Bioactivation -- Hepatotoxicity -- Nephrotoxicity; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2022.05.005
• Languages: English
• ISSNs: 0378-4274

Abstract

Abstract: Mitochondria appeared to be a major target for paracetamol (PAR)-induced hepatotoxicity. Studies suggested that microsomal CYPs catalyse bioactivation of PAR to N -acetyl- p -benzoquinone imine (NAPQI), which alkylates mitochondrial proteins, and causes transmission of death signal from mitochondria to nucleus. We hypothesised that local formation of NAPQI within mitochondria seems more likely compared to the translocation of NAPQI. We therefore tested whether the formation of NAPQI may be catalysed by mitochondrial CYPs. Cellular fractions were isolated from human liver and kidney to compare the metabolic capacities. Liver and kidney mitochondria are capable to generate NAPQI. Mitochondrial CYP2E1 and CYP3A4 activities were comparable to the microsomal counterparts in both organs. Previously reported higher kidney microsomal CYP2E1 activity in men compared women were observed in mitochondrial CYP2E1 as well in the present study. On the other hand, no correlation between kidney CYP2E1 activity and quantity of NAPQI formation, as well as no induction on mitochondrial permeability transition pore (mPTP) opening by PAR in kidney mitochondria strongly suggested a different toxicity mechanism in this organ. Highlights: NAPQI formation is catalysed by mitochondrial CYPs in liver and kidney. Mitochondrial CYP2E1 activity is higher in men compared to women. Kidney mitochondrial CYP2E1 activity did not correlate with the amount of NAPQI. NAPQI did not induce mPTP in kidney in contrast to liver.