Preferential interaction of trans-membrane alpha-helices whose hydrophobic length matches the hydrophobic thickness of the lipid bilayer could be a mechanism of retention in the Golgi apparatus. We have used fluorescence methods to study the interaction of peptides Ac-K2-G-Lm-W-Ln-K2-A-amide (Pm+n) with bilayers of phosphatidylcholines with chain lengths between C14 and C24. The peptide P22 (m = 10, n = 12) incorporates into all bilayers, but P16 (m = 7, n = 9) does not incorporate into bilayers when the fatty acyl chain length is C24 and only partly incorporates into bilayers where the chain length is C22. The strongest binding is seen when the hydrophobic length of the peptide matches the calculated hydrophobic thickness of the bilayer. It is suggested that a too-thin bilayer can match to a too-long peptide both by stretching of the lipid and by tilting of the peptide. However, a too-thick bilayer can only match a too-thin peptide by compression of the lipid, which becomes energetically unfavorable when the difference between the bilayer thickness and the peptide length exceeds about 10 A. The presence of cholesterol in the bilayer leads to a marked reduction in the incorporation of P16 into bilayers where the chain length is C18. Hydrophobic mismatch could explain retention of proteins with short trans-membrane alpha-helical domains in the Golgi, the effect following largely from the low concentration of cholesterol in the Golgi membrane compared to that in the plasma membrane.
Pregnant hamsters were given a single oral dose (35 mumol/kg) of all-trans-retinoic acid, 13-cis-retinoic acid, all-trans-4-oxo-retinoic acid, 9-cis-retinal or all-trans-retinyl acetate during the early primitive streak stage of development. The radioactivity associated with the acidic retinoids was distributed to all tissues sampled (including placenta and fetus), with the largest accumulation in the liver and the least accumulation in fat. Radioactivity from 9-cis-retinal or retinyl acetate concentrated in the liver and lung. The all-trans-retinoic acid was oxidized in vivo to all-trans-4-oxo-retinoic acid and isomerized to 13-cis-retinoic acid: 13-cis-retinoic acid was oxidized to 13-cis-4-oxo-retinoic acid and isomerized to all-trans-retinoic acid. No parent 9-cis-retinal or retinyl acetate could be detected in maternal plasma. Plasma concentrations of the parent acidic retinoids reached their maxima within 60 min and then followed exponential decay. Of all the retinoids examined here, 13-cis-retinoic acid showed the largest area under the plasma curve, the slowest clearance and the longest elimination t1/2. Total plasma radioactivity, consisting of unidentified metabolites, remained elevated at 4 days after dosing. Maternal peak circulating concentrations of the parent retinoids, total radioactivity, plasma pharmacokinetic parameters or the total concentrations of residual radioactivity in fetal tissues could not be correlated with the differential teratogenic potencies of these retinoids.
Repeated injections of gold sodium thiomalate were given to Wistar rats and the effect of gold on the binding of endogenous zinc and copper to the cytosolic proteins in the liver and kidneys was studied. The tissue levels of gold and the tissue uptake of zinc and copper as a function of gold dose was also studied.The result of the multiple-dose study show that in the liver the tissue gold levels rose rapidly following the first five gold injections (one injection/week) and then stabilized. In the kidneys the gold concentrations continued to increase with each additional dose. Uptake of zinc into the high molecular weight proteins (MW > 60,000 daitons) and the supernxide dismutase fractions were significantly increased following the repeated gold injections in the liver and kidney cytosoi. The uptake of copper into the high MW proteins were decreased in the liver as well as the kidneys. Copper levels in the superoxide dlsmutase and the low MW (< 4000 daltons) fractions initially increased then decreased from the sixth gold dose onwards (possibly related to the overall decrease in tissue copper levels in the liver). The incorporation of eopper into the hepatie metallothioneins appeared to be unaltered. In the kidney eytosol, the uptake of copper was significantly increased into the metallothionein fractions. The uptake into the other fractions decreased over the multiple-dose period.Gold sodium thlomalate inereased the tissue eoncentratlon of zinc in the liver as well as the kidneys. The level of copper in the liver was decreased and that in the kidneys increased. Practically all the additional copper in the kidneys was incorporated in the thioneins.These observations indieate that gold sodium thiomalate has a major role in providing a stimulus for the liver, kidney and perhaps other cells to bring about a redistribution of body zlne and copper. The various cytosolic proteins, including the inducible metalloproteins, superoxide dismutase and metallothioneins, seem to help the cell carry out this task. In view of the importanee of these essential metals in physiological processes of relevance to rheumatoid arthritis, it is suggested that gold salts may mediate, to some extent, their antiarthrltic activity through an effect on the metabolism of zinc and copper.
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