Abstract
The purpose of the study was to develop a kinetic method for measurement of different parameters of cholesterol metabolism in man using labeled cholesterol precursors that could initially be incorporated even into the slowly exchangeable cholesterol pool. For this purpose, tritiated water and [2-14C]mevalonate were given to five normocholesterolemic subjects and the activities for serum cholesterol and body water were measured serially for up to eight weeks. Elimination of cholesterol was measured by fecal analysis of neutral and acidic steroids. For comparison, two subjects received a mixture of [4-14C]cholesterol and [2-3H]mevalonate. The data were subjected to multicompartmental analysis by computer, with the assumption that synthesis occurred in two compartments. The rapidly exchangeable cholesterol (pool 1) and the fractional hydrogon transport constant from body water to cholesterol could not be measured directly; therefore, the influence of two different mass transport values was tested. The best fit was obtained with the smaller mass of cholesterol in pool 1 associated with a hydrogen transport constant of 0.700 (32 out of 46 hydrogens originate from water). Kinetic analysis of the data allows estimates of the exchangeable cholesterol mass, flux rates of cholesterol between pools 1 and 2, and synthesis of cholesterol separately in the two pools. The results of computer analysis suggested that, in contrast to what has been assumed earlier on the basis of studies with radiolabelled cholesterol, 22-53% of endogenous cholesterol synthesis took place in pool 2 from body water and that this synthesis tended to correlate with the total body fat mass. The study with [2-3H]mevalonate and [4-14C]cholesterol indicated synthesis in pool 2 to be 20-22% of the total. Up to 50% of the DL[2-14C]mevalonate dose was incorporated into cholesterol. The fractional incorporation of DL-mevalonate into pool 2 was correlated with that of tritiated water, indicating that both precursors studied yielded essentially the same kinetic result.
Highlights
The purposeof the studywas to develop a kinetic method for measurementof different parameters ocfholesterol metabolism in man usinglabeledcholesterol precursorsthatcould initially be incorporated even intothe slowly exchangeable cholesteropl ool
The data were subjected to multicompartmental analysis by computer, with the assumption that synthesis occurred in two compartments
[2-3H]mevalonate.The results reveal that a significant V.N. died suddenly from a recurrence of infarction portion of endogenous cholesterol synthesis occurs onthe42nddaya,ndthestudycouldnot be outside the rapidly mixing cholesterol pool
Summary
Seven adult subjects were studied (Table 1). Five of ambulatory patients 8mCi oftritiated water orally and them were ambulatory during the experiment and re- 50 pCi of [2-14C]mevalonateintravenously (both from ceived a tracer mixture of tritiated water and [2-14C]- the Radiochemical CentreA, mershamE, ngland). HTW Hydrogen transport (mg/day) from the body water to PRE The determination of this parameter implies thatthenumber of water-derived hydrogensamongthehydrogen molecules in endogenously synthesized cholesterol molecules is known. Alo Fractional daily rate of cholesterol removal from pool 1 outfromthe body This value wascalculatedtothe computer solution by dividing. Awzu Proportion of 3H incorporated into cholesterol in pool 2, in percent of total hydrogen incorporationfrom 3 H z 0 into cholesterol inpools 1 and 2 For references for the system theoretical approachandthe solution method see Ref. 1, 34-36
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