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- Title
Cytochrome P450-dependent arachidonic acid metabolism in human kidney.
- Authors
Schwartzman, Michal L.; Martasek, Pavel; Rios, Amelia R.; Levere, Richard D.; Solangi, Karim; Goodman, Alvin I.; Abraham, Nader G.
- Abstract
Cytochrome P450-dependent arachidonic acid metabolism in human kidney cortex from several postmortem subjects has been characterized. Using HPLC and GC/MS, four cytochrome P450-arachidonic acid metabolites were tentatively but not unequivocally identified as epoxyeicosatrienoic acid (EET), dihydroxyeicosatrienoic acid (DI-IT) and 19- and 20-hydroxyeicosatetraenoic acids, suggesting the involvement of two major cytochrome P450 enzymes, epoxygenase and ω/ω-1 hydroxylases. This pattern of metabolism was similar to that found in rabbit and rat kidneys. The formation of these metabolites was dependent on the presence of N ADPH and inhibited by IgG of NADPH-cytochrome P450 (c) reductase. Immunologic studies of renal cytochrome P450 epoxygenase demonstrated that antibodies prepared against human-purified hepatic cytochrome P450 epoxygenase recognized renal enzyme protein and inhibited the enzyme activity by 92%. In contrast, control immunoglobulin did not inhibit renal cytochrome P450 epoxygenase. Antibody inhibition of renal cytochrome P450 epoxygenase demonstrated a degree of conservation of both enzyme proteins between liver and kidney. Antibodies against lauric acid ω/ω-1 hydroxylases (P450ω) inhibited the formation of ω/ω-1 hydroxylase products, 19- and 20-HETEs. Identical qualitative patterns of arachidonic acid metabolites were observed in all cortical microsomes studied. Interindividual variations were observed in the cytochrome P450-dependent arachidonic acid metabolism, and the activities ranged from 0.031 to 5.027 nmol arachidonic acid converted/mg protein/30 min, which is about a 150-fold difference. However, when the specific activities for total cytochrome P450-dependent arachidonic acid metabolism were calculated, two separate groups could be distinguished, high and low metabolizers of arachidonic acid. The range of the low metabolizer of arachidonic acid by cytochrome P450 was 0.15 to 0.23 pmol arachidonic acid converted/pmol P450/min, as compared to the range of the high metabolizer which was 1.38 to 1.93 pmol arachidonic acid converted/pmol P450/min. The interindividual variation observed with respect to arachidonic acid metabolism was also observed in other cytochrome P450 monooxygenase systems studied, aryl hydrocarbon hydroxylase and 7-ethoxyresorufin-O-deethylase. Arachidonate metabolites derived by cytochrome P450 have been shown to possess a wide range of biological activities: these include stimulation of peptide hormone release, inhibition and stimulation of Na+-K+-ATPase, vasoreactivity and mobilization of Ca++. We suggest that the interindividual variations observed in cytochrome P450-dependent arachidonic acid metabolism may play a role in the susceptibility of certain individuals to develop clinical disorders such as essential hypertension.
- Subjects
METABOLISM; CYTOCHROME P-450; CYTOCHROMES; ARACHIDONIC acid; KIDNEYS; KIDNEY cortex; PEPTIDE hormones
- Publication
Kidney International, 1990, Vol 37, Issue 1, p94
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1038/ki.1990.13