Introduction to Human Nutrition

110 Introduction to Human Nutrition

usually in response to an injury or a stimulus that
releases the free precursor, most commonly arachido-
nate. The site of highest eicosanoid concentration
appears to be the seminal fl uid, although some species
have no detectable eicosanoids in semen. Eicosanoids
are second messengers modulating, among other
pathways, protein phosphorylation. The lung is a
major site of eicosanoid inactivation.
Four important characteristics of eicosanoid action
should be noted. First, individual eicosanoids often
have biphasic actions as one moves from very low
through to higher, often pharmacological, concentra-
tions. Thus, effects can vary dramatically depending
not only on the experimental system but also on the
eicosanoid concentration used. Second, several of the
more abundant eicosanoids arising from the same
precursor fatty acid have opposite actions to each
other. For instance, prostacyclin and thromboxane
A 2 are both derived from arachidonate but the
former originates primarily from the endothelium
and inhibits platelet aggregation, while the latter orig-
inates primarily from platelets and is a potent plate-
let-aggregating agent. Third, competing eicosanoids

derived from dihomo-γ-linolenate (1 series) and from

eicosapentaenoate (3 series) often have effects that

oppose those derived from arachidonate (2 series)

(Figures 6.14 and 6.15). Thus, unlike prostaglandin

E 2 , prostaglandin E 1 has anti-infl ammatory actions,

reduces vascular tone, and inhibits platelet aggrega-

tion. Fourth, varying the ratio of the precursor fatty

acids in the diet is an effective way to modify eico-

sanoid production. Thus, eicosapentaenoate and

dihomo-γ-linolenate inhibit the synthesis of 2 series

eicosanoids derived from arachidonate. This occurs

by inhibiting arachidonate release from membranes

by phospholipase A 2 and its cascade through the

cyclooxygenases and lipoxygenases. The overproduc-

tion of 2 series eicosanoids is associated with higher

blood pressure, increased platelet aggregation, and

infl ammatory processes, and can be effectively inhib-

ited by dietary approaches using oils rich in eicosap-

entaenoate and γ-linolenate (18:3n-6), the precursor

to dihomo-γ-linolenate.

Stable analogues of some classical prostaglandins

have specialized medical applications, including the

termination of pregnancy and the closing of a patent

Membrane

arachidonic acid

Phospholipase A 2

Free arachidonic acid

Lipoxygenase Cyclooxygenase

HPETEs PGG 2

PGH 2

TXA 2

HETEs

Peroxidase

Hepoxylins

Leukotrienes Lipoxins

PGs PGI 2

Figure 6.14 The arachidonic acid cascade

is a fundamental component of cell signal-

ing during injury. Phospholipase A 2 is

immediately activated and the free arachi-

donic acid thus released is accessible to a

controlled peroxidation process involving

several cyclooxygenases (constitutive or

inducible) and lipoxygenases. Over 50

metabolically active products are poten-

tially produced, depending on the tissue

involved, the type of cell that has been

stimulated, and the type of injury. Only the

main classes of these metabolites are

shown. Before excretion, they are further

metabolized to stable products that are

not shown. Several of the cyclooxygenase

products are competitive with each other,

such as the platelet-aggregating and

blood vessel wall-constricting effects of

thromboxane A 2 (TXA 2 ) produced in plate-

lets, versus the opposite effects of prosta-

cyclin (PGI 2 ) derived from the blood vessel

wall. HETE, hydroxyeicosatetraenoic acid;

HPETE, hydroperoxyeicosatetraenoic acid;

PG, prostaglandin; TX, thromboxane.