Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity.
Flutamide, a widely used nonsteroidal anti-androgen, but not its bioisostere bicalutamide, has been associated with idiosyncratic drug-induced liver injury. Although the susceptibility factors are unknown, mitochondrial injury has emerged as a putative hazard of flutamide. To explore the role of mitochondrial sensitization in flutamide hepatotoxicity, we determined the effects of superimposed drug stress in a murine model of underlying mitochondrial abnormalities. Male wild-type or heterozygous Sod2(+/-) mice were injected intraperitoneously with flutamide (0, 30 or 100 mg/kg/day) for 28 days. A kinetic pilot study revealed that flutamide (100 mg/kg/day) caused approximately 10-fold greater exposure than the reported therapeutic mean plasma levels. Mutant (5/10), but not wild-type, mice in the high-dose group exhibited small foci of hepatocellular necrosis and an increased number of apoptotic hepatocytes. Hepatic GSSG/GSH, protein carbonyl levels, and serum lactate levels were significantly increased, suggesting oxidant stress and mitochondrial dysfunction. Measurement of mitochondrial superoxide in cultured hepatocytes demonstrated that mitochondria were a significant source of flutamide-enhanced oxidant stress. Indeed, mitochondria isolated from flutamide-treated Sod2(+/-) mice exhibited decreased aconitase activity as compared to vehicle controls. A transcriptomics analysis using MitoChips revealed that flutamide-treated Sod2(+/-) mice exhibited a selective decrease in the expression of all complexes I and III subunits encoded by mitochondrial DNA. In contrast, Sod2(+/-) mice receiving bicalutamide (50 mg/kg/day) did not reveal any hepatic changes. These results are compatible with our concept that flutamide targets hepatic mitochondria and exerts oxidant stress that can lead to overt hepatic injury in the presence of an underlying mitochondrial abnormality.
University of Connecticut School of Pharmacy, Department of Pharmaceutical Sciences, Storrs, CT 06269, USA.
Rohini
R
Kashimshetty
Varsha G
VG
Desai
Vijay M
VM
Kale
Taewon
T
Lee
Carrie L
CL
Moland
William S
WS
Branham
Lee S
LS
New
Eric C Y
EC
Chan
Husam
H
Younis
Urs A
UA
Boelsterli
D000410:Alanine Transaminase / Q000187:drug effects / Q000378:metabolism; D000726:Androgen Antagonists / Q000633:toxicity; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005485:Flutamide / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006579:Heterozygote; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009336:Necrosis / Q000139:chemically induced; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D013482:Superoxide Dismutase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D049490:Systems Biology; D014105:Tosyl Compounds / Q000494:pharmacology; D000099156:Superoxide Dismutase 2
D000410:Alanine Transaminase; D000726:Androgen Antagonists; D000813:Anilides; D005485:Flutamide; D009570:Nitriles; D013482:Superoxide Dismutase; D014105:Tosyl Compounds; D000099156:Superoxide Dismutase 2; C053541:bicalutamide