Medical Research Society
gastric ulcers. The effect of the drug on individual
human pepsins and pepsinogens has therefore been
studied.
The results show that carbenoxolone, in suspension
at pH 4.0, inhibits swine pepsin A, and human
pepsins 1, 3 and 5. Human pepsin 5 is the most
readily inhibited, and human pepsin 1 the least.
Inhibition occurs by a process which is time-dependent,
temperature-dependent and proportional to the
quantity of carbenoxolone suspended.
Carbenoxolone, in solution at pH 7.4 and pH 8.0,
inhibits the total pepsinogens of human gastric mucosal
extracts and inhibits the individual pepsinogens 1,
3 and 5. Pepsinogen 1 was the most readily inhibited,
pepsinogen 5 the least. Chymotrypsin was readily
inhibited by carbenoxolone at pH 7-4 and 8.0.
Trypsin was not inhibited at pH 7-4but was inhibited,
relatively weakly, at pH 8.0. Pronase was inhibited
weakly at pH 7.4 and 8.0, but papain was weakly
activated.
Carbenoxolone is therefore not a general enzyme
inhibitor but shows specificity for enzymes (pepsins
and chymotrypsin) which split proteins at the same
bonds, rather than for enzymes with similar active
centres (chymotrypsin and trypsin).
The results suggest that, in vivo, carbenoxolone
might diminish peptic activity in three ways: by
inhibiting pepsinogens irreversibly in the mucosal
cells or at some point before their activation to
pepsins ;by inhibiting pepsins irreversibly in the gastric
lumen; and by binding pepsins in the lumen without
destroying their activity but reducing their effective
concentration.
These results are compatible with the hypotheses that
pepsins, and pepsin 1 particularly, are factors in the
aetiology of peptic ulcer.
14. INFLUENCE O F SATURATED AND UNSATURATED DIETARY FAT ON DIURNAL
CHANGES IN PLASMA TRIGLYCERIDE AND
LIPOPROTEIN LEVELS
and B. LEWIS
A. CHAIT, E. RABAYA,
A. FEBRUARY
Departments of Chemical Pathology and Medicine,
Royal Postgraduate Medical School, London W12 OHS
There is presumptive evidence that prebeta-hyperlipoproteinaemia is a risk factor for ischaemic heart
disease (Carlson & Bottinger, 1972, Lancet, i, 865).
We have previously reported to the Society evidence
that prebeta-lipoprotein not only contains endogenous
triglyceride but also contributes to the transport of
dietary fat in plasma (February et al., 1972, Clinical
.
these reasons, it is important
Science, 43, 4 ~ ) For
to know the behaviour of prebeta-lipoprotein levels
in the fed as well as the fasted state. In this study,
we have examined the influence of fat intake, both
saturated and polyunsaturated, on plasma levels of the
triglyceride-bearing lipoproteins in six normal
subjects and in six patients with primary prebetalipoproteinaemia. Little is known of the effects of
7P
dietary fats on plasma triglyceride secretion and removal; we have therefore employed the intravenous fat
tolerance test and have measured post-heparin lipolytic
activity to assess the removal of triglyceride from
plasma. Lipid measurements were made on ultracentrifugally-isolated Sf >400, 100-400, 20-100, and
0-12 lipoprotein fractions from plasma. Subjects
received isocaloric diets containing 40% fat calories
and 45% carbohydrate calories; in one 10-day
feeding period, the fat was chiefly saturated (P/S
ratio <0.15), and this was followed or preceded by a
similar period of polyunsaturated fat feeding (P/S
ratio >2.0). Body weight was not signilicantly
different at the end of each period. On the last day of
each feeding period, blood samples were analysed at
intervals of 1-3 h.
At the end of the high P/S period, fasting plasma
triglycerideand cholesterol levels were 41% ( P e 0.005)
and 22% (PeO.005) lower, respectively, than after
the saturated-fat period. This was associated with
reduction in Sf 20-400 and Sf 0-20 (prebeta- and
beta-) lipoproteins and occurred in all normal and
hyperlipidaemic subjects. In most subjects the type of
dietary fat had an even greater influence on postprandial triglyceride levels than fasting levels.
The mean fractional removal rate of injected
triglyceride (fat tolerance test) was not different during
the saturated fat period (0036 min-I) and the unsaturated fat period (0.034 min-'). Nor was postheparin lipolytic activity in plasma correlated with
changes in plasma triglyceride level. These iindings
suggest that the effect of polyunsaturated fat in
reducing plasma levels of endogenous triglyceride is
not mediated by increased removal of triglyceride,
but rather by diminished secretion into plasma.
Impaired peripheral uptake of triglyceride from
plasma is believed to be an important mechanism in
the primary hypertriglyceridaemias. The fall of plasma
triglyceride when saturated fat was replaced by polyunsaturated fat was greater in our subjects with
highest initial levels. This may be due to an interaction
between dietary effects on secretion rate and intrinsic
differences in removal rate.
15. FACTORS AFFECTING GLUCOSE AND
KETONE BODY UTILIZATION BY HUMAN
ADIPOSE TISSUE
A. KISSEBAH,
B. TULLOCH,
N. VYDELINGUM
and R.
FRASER
Royal Postgraduate Medical School, Hammersmith
Hospital, Ducane Road, London W12 OHS
Ketone bodies are manufactured primarily in the liver
and transported through blood t o peripheral tissues
where they are readily oxidized. The regulation of
production of ketones by the liver has been extensively
studied both in vivo and in vitro (Campbell & Best,
1956; Krebs, 1966; Wieland, 1968). However, little is
known about factors controlling the peripheral utilization of ketone bodies. Earlier work in several