Nonalcoholic steatosis and steatohepatitis. II. Cytochrome P-450 enzymes and oxidative stress.
Oxidative stress is present in the liver of humans with steatosis and nonalcoholic steatohepatitis (NASH) and is a plausible mediator of cellular injury, inflammatory recruitment, and fibrogenesis. CYPs 2E1 and 4A are the microsomal oxidases involved with fatty acid oxidation. Both enzymes can reduce molecular oxygen to produce prooxidant species, which, if not countered efficiently by antioxidants, create oxidative stress. In this theme article, we present the evidence that, in the context of hepatic steatosis, CYPs 2E1 and 4A could generate the "second hit" of cellular injury, particularly when antioxidant reserves are depleted, and propose ways in which this could contribute to the pathogenesis of NASH.
Robertson
G
G
Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia.
Leclercq
I
I
Farrell
G C
GC
D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism*; D006505:Hepatitis / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000502:physiology; D015854:Up-Regulation
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D019392:Cytochrome P-450 CYP2E1; D042926:Cytochrome P-450 CYP4A