In 1929 Burr and Burr discovered the
essential fatty acids omega-6 and omega-3. Since then, researchers have shown a growing interest in
polyunsaturated fatty acids (PUFA) as precursors of "
lipid mediator" molecules, often with opposing effects,
prostaglandins,
prostacyclins,
thromboxanes,
leukotrienes, lipossines, resolvines, protectines, maresins that regulate immunity, platelet aggregation,
inflammation, etc. They showed that the balance between omega-3 and omega-6
acids has a profound influence on all the body's inflammatory responses and a raised level of PUFA omega-3 in tissue correlate with a reduced incidence of degenerative
cardiovascular disease, some
mental illnesses such as depression, and neuro-degenerative diseases such as Alzheimer's. The CYP-catalyzed epoxidation and hydroxylation of
arachidonic acid (AA) were established recently as the so-called third branch of AGE cascade.
Cytochrome P450 (CYP) epoxygenases convert AA to four epoxyeicosatrienoic
acid (EET) regioisomers, that produce vascular relaxation anti-inflammatory effects on blood vessels and in the kidney, promote angiogenesis, and protect ischemic myocardium and brain.
Eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA) are accessible to CYP
enzymes in the same way as AA. Metabolites derived from EPA include epoxye-icosatetraenoic
acids (EETR) and hydroxyeicosapentaenoic
acids (19- and 20-HEPE), whereas DHA include epoxydocosapentaenoic
acids (EDPs) hydroxydocosahexaenoic
acids (21- and 22-HDoHE). For many of the CYP
isoforms, the n-3 PUFAs are the preferred substrates and the available data suggest that some of the vasculo- and cardioprotective effects attributed to dietary n-3 PUFAs may be mediated by CYP-dependent metabolites of EPA and DHA. From AA derives also
endocannabinoids like
anandamide (
N-arachidonoylethanolamine) and
2-arachidonoylglycerol, capable of mimicking the pharmacological actions of the active principle of Cannabis sativa preparations such as hashish and marijuana (-)-Delta9-tetrahydrocannabinol. They act as true 'endogenous
cannabinoids' by binding and functionally activating one or both
cannabinoid receptor present on nervous and peripheral cell membranes.
Enzymes that carry out
anandamide oxidation are the same
fatty acid oxygenases that are known to act on endogenous
arachidonic acid namely, the members of the COX, LOX, and P450 families of
enzymes. Recent advances in the biochemistry and pharmacology of the
endocannabinoid system, also for its central and peripheral roles in regulating food intake, will offer the development of novel therapeutic agents.