Differential metabolism of 4-hydroxynonenal in liver, lung and brain of mice and rats.
The lipid peroxidation end-product 4-hydroxynonenal (4-HNE) is generated in tissues during oxidative stress. As a reactive aldehyde, it forms Michael adducts with nucleophiles, a process that disrupts cellular functioning. Liver, lung and brain are highly sensitive to xenobiotic-induced oxidative stress and readily generate 4-HNE. In the present studies, we compared 4-HNE metabolism in these tissues, a process that protects against tissue injury. 4-HNE was degraded slowly in total homogenates and S9 fractions of mouse liver, lung and brain. In liver, but not lung or brain, NAD(P)+ and NAD(P)H markedly stimulated 4-HNE metabolism. Similar results were observed in rat S9 fractions from these tissues. In liver, lung and brain S9 fractions, 4-HNE formed protein adducts. When NADH was used to stimulate 4-HNE metabolism, the formation of protein adducts was suppressed in liver, but not lung or brain. In both mouse and rat tissues, 4-HNE was also metabolized by glutathione S-transferases. The greatest activity was noted in livers of mice and in lungs of rats; relatively low glutathione S-transferase activity was detected in brain. In mouse hepatocytes, 4-HNE was rapidly taken up and metabolized. Simultaneously, 4-HNE-protein adducts were formed, suggesting that 4-HNE metabolism in intact cells does not prevent protein modifications. These data demonstrate that, in contrast to liver, lung and brain have a limited capacity to metabolize 4-HNE. The persistence of 4-HNE in these tissues may increase the likelihood of tissue injury during oxidative stress.
Pharmacology and Toxicology, Rutgers University-Ernest Mario School of Pharmacy, Piscataway, NJ, USA.
Ruijin
R
Zheng
Pharmacology and Toxicology, Rutgers University-Ernest Mario School of Pharmacy, Piscataway, NJ, USA.
Ana-Cristina
AC
Dragomir
Pharmacology and Toxicology, Rutgers University-Ernest Mario School of Pharmacy, Piscataway, NJ, USA.
Vladimir
V
Mishin
Environmental & Occupational Medicine, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ, USA.
Jason R
JR
Richardson
Environmental Science, School of Health Sciences and Practice, New York Medical College, Valhalla, NY, USA.
Diane E
DE
Heck
Pharmacology and Toxicology, Rutgers University-Ernest Mario School of Pharmacy, Piscataway, NJ, USA.
Debra L
DL
Laskin
Environmental & Occupational Medicine, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ, USA. Electronic address: jlaskin@eohsi.rutgers.edu.
Jeffrey D
JD
Laskin
D000447:Aldehydes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D020318:Rats, Long-Evans; D013045:Species Specificity; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism
D000447:Aldehydes; D019138:Antibodies, Blocking; D004791:Enzyme Inhibitors; D005982:Glutathione Transferase; C027576:4-hydroxy-2-nonenal
4-Hydroxynonenal; Alcohol dehydrogenase; Lipid peroxidation; Neurotoxicity; Pulmonary toxicity; Reactive oxygen species