Effects of the hypocholesteremic agent trifluperidol on the sterol, steryl ester, and fatty acid metabolism of Saccharomyces cerevisiae

Abstract

Trifluperidol (TFP), at a concentration of 100 ,M, inhibited the 24-h growth of Saccharomyces cerevisiae by about 30%. Effects on lipid metabolism were investigated by monitoring the incorporation of [1-14C]sodium acetate into various lipid fractions after 4 and 24 h of growth in the presence of several concentrations of TFP. Although little effect was noted on the amount of free sterols, 24-h incorporation of label into steryl esters was increased two-to fourfold by 100 ,M TFP. Major sterol components of the steryl ester fraction isolated from an untreated culture were zymosterol (48%) and ergosterol (24%), whereas from the TFP-treated culture A8 24(28)-ergostadienol (66.6%) and A8-ergostenol (14.7%) were most abundant. Free sterols present in the highest concentration in the untreated culture were ergosterol (78.2%) and lanosterol (13%); whereas A8'22_ ergostadienol (38.5%), A8-ergostenol (35.4%), and A8' 24(281-ergostadienol (25.4%) were the most abundant free sterols obtained from the TFP-treated culture. Thus, the major block in the sterol biosynthetic pathway in yeast appears to be A8-> A7 isomerization. In these same cultures the relative amounts of C12 and C14 acids isolated from both steryl ester and miscellaneous lipid fractions were increased more than threefold over controls.

High affinity of sigma1‐binding sites for sterol isomerization inhibitors: evidence for a pharmacological relationship with the yeast sterol C8–C7 isomerase

“…The haloperidol analogue trifluperidol is clinically used as an antipsychotic. Besides its prominent antidopaminergic activity trifluperidol also inhibits the yeast sterol C 8 –C 7 isomerase (Sobus et al , 1977). It differs from haloperidol by a trifluoromethyl group instead of a chlorine atom and has modestly lower affinity ( K i 0.83 ± 0.24 n m ( n = 3)) than haloperidol ( K i 0.2 n m (Hanner et al , 1996)) for the liver (+)‐[ 3 H]‐pentazocine binding site (Table 1, Figure 2a).…”

“…The ultrahigh affinity of fenpropimorph for the brain α 1 ‐site ( K i 5 p m ) suggests that this morpholine might be a valuable tool for studies on sigma 1 ‐mediated effects. The haloperidol congener trifluperidol ( K i 1.3 n m ) inhibits the sterol C 8 –C 7 isomerase of yeast (Sobus et al , 1977) whereas the azadecalin MDL28,815 ( K i 0.16 n m ) inhibits the mammalian sterol C 8 –C 7 isomerase in 3T3 mouse fibroblasts (Gerst et al , 1988) as well as in the human hepatoma cell line HepG2 (van Sickle et al , 1993). The anti‐hypercholesteraemic drug AY‐9944 ( K i 0.46 n m ) reduces sterol C 8 –C 7 isomerization in yeast (Pereira et al , 1983) and rat adrenal gland (Givner et al , 1967).…”

Measurement in vitro of the esterification of yeast sterols

“…Although hydrolase enzyme is observed, the low activity would fail to account for the pool of free sterols present in the cells during the early growth phases. Yeast cultured under growth inhibitory conditions caused by trifluperidol also accumulate sterol esters (14). Thus, esterification cannot be caused simply by exhaustion of growth nutrients from the culture medium.…”

The effects of the hypocholesteremic compound 3β‐(β‐dimethylaminoethoxy)‐androst‐5‐en‐17‐one on the sterol and steryl ester composition ofSaccharomyces cerevisiae

“…The effect of DMAE-DHA concentration on the extent of total sterol esterification is also of interest. Earlier work indicated that exposure of yeast to either trifluperidol (20) or triparanol (21) resulted in the production of at least twice as much esterified sterol as in control cultures. The increased sterol esterification occurring in the presence of these drugs may be due to the accumulation of A8 sterols, since they appear to be better substrates than ergosterol for esterification (22).…”