28 SECTION ICellular & Molecular Basis of Medical Physiology
Dehydrogenation of fats is known to occur in the body, but there
does not appear to be any synthesis of carbon chains with the ar-
rangement of double bonds found in the essential fatty acids.
EICOSANOIDS
One of the reasons that essential fatty acids are necessary for
health is that they are the precursors of prostaglandins, prosta-
cyclin, thromboxanes, lipoxins, leukotrienes, and related com-
pounds. These substances are called eicosanoids, reflecting
their origin from the 20-carbon (eicosa-) polyunsaturated fat-
ty acid arachidonic acid (arachidonate) and the 20-carbon
derivatives of linoleic and linolenic acids.
The prostaglandins are a series of 20-carbon unsaturated
fatty acids containing a cyclopentane ring. They were first iso-
lated from semen but are now known to be synthesized in most
and possibly in all organs in the body. Prostaglandin H 2
(PGH 2 ) is the precursor for various other prostaglandins,
thromboxanes, and prostacyclin. Arachidonic acid is formed
from tissue phospholipids by phospholipase A 2. It is converted
to prostaglandin H 2 (PGH 2 ) by prostaglandin G/H synthases
1 and 2. These are bifunctional enzymes that have both cyclo-
oxygenase and peroxidase activity, but they are more com-
monly known by the names cyclooxygenase 1 (COX1) and
cyclooxygenase 2 (COX2). Their structures are very similar,
but COX1 is constitutive whereas COX2 is induced by growth
factors, cytokines, and tumor promoters. PGH 2 is converted to
prostacyclin, thromboxanes, and prostaglandins by various tis-
sue isomerases. The effects of prostaglandins are multitudinous
and varied. They are particularly important in the female
reproductive cycle, in parturition, in the cardiovascular system,
in inflammatory responses, and in the causation of pain. Drugs
that target production of prostaglandins are among the most
common over the counter drugs available (Clinical Box 1–5).
Arachidonic acid also serves as a substrate for the produc-
tion of several physiologically important leukotrienes and
lipoxins. The leukotrienes, thromboxanes, lipoxins, andCLINICAL BOX 1–4
Cholesterol & Atherosclerosis
The interest in cholesterol-lowering drugs stems from the
role of cholesterol in the etiology and course of athero-
sclerosis. This extremely widespread disease predisposes
to myocardial infarction, cerebral thrombosis, ischemic
gangrene of the extremities, and other serious illnesses. It is
characterized by infiltration of cholesterol and oxidized
cholesterol into macrophages, converting them into foam
cells in lesions of the arterial walls. This is followed by a
complex sequence of changes involving platelets, macro-
phages, smooth muscle cells, growth factors, and inflam-
matory mediators that produces proliferative lesions which
eventually ulcerate and may calcify. The lesions distort the
vessels and make them rigid. In individuals with elevated
plasma cholesterol levels, the incidence of atherosclerosis
and its complications is increased. The normal range for
plasma cholesterol is said to be 120 to 200 mg/dL, but in
men, there is a clear, tight, positive correlation between the
death rate from ischemic heart disease and plasma choles-
terol levels above 180 mg/dL. Furthermore, it is now clear
that lowering plasma cholesterol by diet and drugs slows
and may even reverse the progression of atherosclerotic le-
sions and the complications they cause.
In evaluating plasma cholesterol levels in relation to athero-
sclerosis, it is important to analyze the LDL and HDL levels as
well. LDL delivers cholesterol to peripheral tissues, including
atheromatous lesions, and the LDL plasma concentration cor-
relates positively with myocardial infarctions and ischemic
strokes. On the other hand, HDL picks up cholesterol from pe-
ripheral tissues and transports it to the liver, thus lowering
plasma cholesterol. It is interesting that women, who have a
lower incidence of myocardial infarction than men, have
higher HDL levels. In addition, HDL levels are increased in indi-
viduals who exercise and those who drink one or two alco-
holic drinks per day, whereas they are decreased in individuals
who smoke, are obese, or live sedentary lives. Moderate drink-
ing decreases the incidence of myocardial infarction, and obe-
sity and smoking are risk factors that increase it. Plasma cho-
lesterol and the incidence of cardiovascular diseases are
increased in familial hypercholesterolemia, due to various
loss-of-function mutations in the genes for LDL receptors.CLINICAL BOX 1–5
Pharmacology of Prostaglandins
Because prostaglandins play a prominent role in the genesis
of pain, inflammation, and fever, pharmacologists have long
sought drugs to inhibit their synthesis. Glucocorticoids in-
hibit phospholipase A 2 and thus inhibit the formation of all
eicosanoids. A variety of nonsteroidal anti-inflammatory
drugs (NSAIDs) inhibit both cyclooxygenases, inhibiting the
production of PGH 2 and its derivatives. Aspirin is the best-
known of these, but ibuprofen, indomethacin, and others are
also used. However, there is evidence that prostaglandins
synthesized by COX2 are more involved in the production of
pain and inflammation, and prostaglandins synthesized by
COX1 are more involved in protecting the gastrointestinal
mucosa from ulceration. Drugs such as celecoxib and rofe-
coxib that selectively inhibit COX2 have been developed,
and in clinical use they relieve pain and inflammation, possi-
bly with a significantly lower incidence of gastrointestinal ul-
ceration and its complications than is seen with nonspecific
NSAIDs. However, rofecoxib has been withdrawn from the
market in the United States because of a reported increase of
strokes and heart attacks in individuals using it. More re-
search is underway to better understand all the effects of the
COX enzymes, their products, and their inhibitors.