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J A Olson

Publications and source records attributed to J A Olson.

At least 91 records · Page 5Linked to original sources
PubMed1993

Molecular actions of carotenoids.

Carotenoids can be attacked enzymatically at almost every position in the molecule. On the other hand, under dark nonoxidative conditions, they can be very stable. Thus, the precise chemical and biological environment is of crucial importance in determining whether, and how, they are transformed. Three important biologically active derivatives of carotenoids, vitamin A, trisporic acid and abscisic acid, all of which serve as hormones in appropriate cells, are, or can be, formed from precursor carotenoids. Highly active forms of all three hormones are 9-cis isomers. In all cases, the products are involved both in light-induced reactions as well as in cellular differentiation, often related to sexual maturation. Each of these hormones is formed by an initial dioxygenase attack on the central conjugated chain of carotenoids followed by a series of specific reactions. Indeed, when various carotenoids of different structure are studied in humans, each shows a characteristic, if not unique, set of metabolites. Thus, generalizations about carotenoid metabolism must be constrained by precise metabolic information about given compounds. In dealing with the manifold biological activities of carotenoids, it is useful to categorize them as functions, actions or associations. In the hope of gaining greater insight into the relationship between carotenoids, health and longevity, these distinctions should be helpful.

Abscisic Acid↗
PubMed1993

New simplified procedures for the extraction and simultaneous high-performance liquid chromatographic analysis of retinol, tocopherols and carotenoids in human serum.

A short, simple extraction procedure and a sensitive reversed-phase high-performance liquid chromatographic assay, which utilizes isocratic elution and detection either by a photodiode-array detector or by two detectors set at 300 and 450 nm, have been developed to measure retinol, tocopherols and several carotenoids in human serum simultaneously. By relying on characteristic UV-visible spectra, seventeen carotenoids, retinol and alpha- and gamma-tocopherols were identified in concentrated serum extracts by use of the three-dimensional data mode of a photodiode-array detector. The presence of some recently reported carotenoids in human serum has been confirmed.

Carotenoids↗
PubMed1993

Comparative teratogenicity and metabolism of all-trans retinoic acid, all-trans retinoyl beta-glucose, and all-trans retinoyl beta-glucuronide in pregnant Sprague-Dawley rats.

When single large equimolar doses (0.38-0.41 mmol/kg BW) of all-trans retinoic acid (RA), all-trans retinoyl beta-glucose (RBGL), and all-trans retinoyl beta-glucuronide (RBG) are administered orally in oil on day 8.5 of pregnancy to Sprague-Dawley rats, RA and RBGL proved highly teratogenic, whereas RBG was not. Indeed, fetuses from RBG-treated dams were 16% heavier (P < 0.01) than control fetuses. After dosing with RA and RBGL, RA appeared in large amounts within 0.5 h in the maternal plasma and within 1.0 h in the embryo. In contrast, orally administered RBG seemed to be absorbed much more slowly, to be converted very slowly to RA, and not to accumulate either as RBG or as RA in the embryo. When incubated in vitro with embryos and attached membranes, however, both all-trans RBG and all-trans RA were partially converted to 13-cis RA. The nonteratogenicity of RBG, in contrast to RA, seems to be due to a much slower rate of GI absorption, a slow rate of hydrolysis to RA, a limited passage from the maternal circulation into the embryo, and a lower inherent toxicity.

Abnormalities, Drug-Induced↗
PubMed1993

Vitamin A and carotenoids as antioxidants in a physiological context.

Under selected conditions, vitamin A and carotenoids can both accept and donate electrons, and carotenoids can also quench singlet oxygen. Thus both sets of compounds can theoretically participate in a biological antioxidant network. Under physiological conditions, vitamin A esters are transported and stored in a lipid matrix that contains other antioxidants, and retinol and its active metabolites are largely bound in clefts of specific retinoid-binding proteins. Thus, vitamin A seems to be protected in vivo by other antioxidants and proteins rather than protecting other molecules. Carotenoids are largely distributed in lipoproteins, membranes, and the lipid phases of intracellular structures, usually together with vitamin E. Carotenoids can interact with other antioxidants in vitro, but whether they play similar significant roles in vivo is not clear. Nonetheless, some genetic conditions and precancerous lesions respond to carotenoids, and the dietary intake of carotenoids has been associated with a reduced risk of several chronic diseases. Carotenoids seem to act per se in such systems rather than by their conversion into vitamin A.

Animals↗
PubMed1992

Synthetic modification of a novel microbial ionophore: exploration of anticoccidial structure-activity relationships.

While fermentation-derived polyether ionophores such as salinomycin are the dominant class of anticoccidial feed additives, there is little information concerning the structural features which confer optimal potency/efficacy in this important series. The recently discovered microbial polyether 1a, featuring potent, broad-spectrum anticoccidial activity, was employed as a template to explore structure-activity relationships. A number of single-step synthetic modifications targeted structural changes in both the lipophilic carbon backbone and the ion-binding cavity of 1a. Although previous semisynthetic transformations among the polyether ionophores almost always resulted in a substantial loss of anticoccidial activity, we obtained several analogues, altered on the periphery of the ionophore-ion complex, which retain good potency and efficacy. Monoglycone 7 (semduramicin sodium) has the most impressive anticoccidial profile of this series, and is undergoing further biological testing under field conditions.

Animals↗
PubMed1992

Retinoyl beta-glucuronide: lack of binding to receptor proteins of retinoic acid as related to biological activity.

Retinoid beta-glucuronides have emerged as biologically active, water-soluble, natural retinoids with relatively few toxic and teratogenic effects. The mechanism of action of these glucuronides in the control of epithelial differentiation, growth, and tumorigenesis is unknown. Since retinoyl beta-glucuronide (RAG) contains a free carboxyl group, we studied the interactions of RAG with cellular retinoic acid-binding protein (CRABP) and nuclear receptors of retinoic acid (RARs), the possible mediators of the biological action of retinoic acid (RA). RAG did not exhibit any significant affinity to bind either CRABP or RARs. During 24- and 48-hr incubations of RAG in chick cytosol, detectable amounts of RA were generated which interacted with the RA receptors. In chick skin, the biological activity of RAG may be due to this slowly released RA. Other possible modes of action of RAG are suggested.

Animals↗
PubMed1992

Metabolism of carotenoid analogs in humans.

Single oral doses (100 mumol) in peanut oil of 4,4'-dimethoxy-beta-carotene, ethyl beta-apo-8'-carotenoate, and beta-apo-8'-carotenal were administered to healthy adult male subjects (n = 4-6). Blood samples were taken frequently thereafter, and serum carotenoids and retinoids were analyzed by HPLC. The metabolism of the three analogs was very different; 4,4'-dimethoxy-beta-carotene was oxidized at the 4 and 4' positions but apparently not cleaved, whereas ethyl beta-apo-8'-carotenoate was not detectably metabolized, and beta-apo-8'-carotenal was extensively converted to its corresponding acid, alcohol, and fatty acyl ester and detectably converted to retinyl ester and possibly to two shorter beta-apocarotenals. Serum concentrations of endogenous retinoids and carotenoids, except as noted above, were not affected in any case. Kinetically, the maximum serum concentrations, areas under the curve, and mean sojourn times for the three analogs differed by 50-, 270-, and 5-fold, respectively. For any given analog, however, the fractional standard deviations for these parameters were only 0.2-0.5.

Administration, Oral↗
PubMed1992

Enhancement of biological activity by conjugation reactions.

Conjugation reactions, such as the formation of sulfates, glucuronides and amino acid derivatives of biologically active compounds, are classically considered as detoxication processes. In essence, common nonpolar compounds are rendered less active by the formation of water-soluble metabolites, which then can readily be excreted in the urine. In the past decade, however, it has become clear that some natural metabolites become more active rather than less so by the formation of such conjugates. Several compounds in this special group will be considered in this article; namely, glucuronide and hydroxyphenylamide conjugates of retinoic acid, glutathione and cysteine conjugates of halogenated hydrocarbons, glucuronide conjugates of various xenobiotics and polyglutamates of folic acid and its inhibitors. The metabolism, biological activity and toxicity of the parent molecule is profoundly affected in complex ways by such reactions. Thus, the historical concept of conjugation reactions as general detoxication processes is no longer tenable.

Animals↗
PubMed1992

CP-72,588, a semisynthetic analog of the polyether ionophore UK-58,582 with increased anticoccidial potency.

We have employed semisynthesis to enhance the anticoccidial potency of a polyether ionophore. CP-72,588 is the alpha-methyl analog of the fermentation-derived polyether ionophore UK-58,852. The parent ionophore required a dose of 15 ppm to achieve anticoccidial efficacy in chickens equivalent to that of salinomycin at 60 ppm. CP-72,588 demonstrated substantially improved potency, with efficacy at 5 to 7.5 ppm. The intrinsic antimicrobial potencies of the two ionophores are similar; however, CP-72,588 was found in chicken tissues at higher levels than those of the parent ionophore when each was administered at the same dose (8 ppm). The enhanced potency of CP-72,588 may be partially due to enhanced uptake into tissues.

Animals↗
PubMed1992

In vivo expression of in vitro anticoccidial activity.

Large-scale screening has led to the identification of several experimental compounds that have very potent intrinsic activity against coccidia, but the lack of translation to in vivo efficacy has been a major hurdle in developing such leads into effective new drugs. We developed methods to explore the impact of oral availability and appropriate distribution in tissue, both of which are potentially important factors in the expression of activity in vivo. For the compounds that we examined, neither oral absorption nor distribution to the site of infection appeared to be the critical barrier to in vivo expression of intrinsic anticoccidial activity. Elucidation of the nature of additional factors that might be involved could assist greatly in the identification of useful new anticoccidial agents.

Administration, Oral↗
PubMed1992

Further investigation of anticoccidial activity of 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine.

The clonidine analog 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine exhibits potent activity against Eimeria tenella infections in chickens. Disease control was abrogated by a selective alpha 2 antagonist, which is consistent with the dependence of such activity upon binding to receptors with characteristics of the vertebrate alpha 2 adrenoceptor. Lack of significant activity against the parasite in tissue culture and our inability to detect significant binding of alpha 2 adrenergic ligands to E. tenella imply that the anticoccidial action may be an indirect effect mediated by the host. Efficacy varied, depending upon the Eimeria species, being greatest for the cecal species E. tenella and less for the intestinal species. The effects described differ substantially from previous accounts of adrenergic actions on parasitic protozoa. The evidence suggests that we have observed a new mechanism of action for antiparasitic drugs.

Adrenergic alpha-Agonists↗
PubMed1992

An unusual pagC::TnphoA mutation leads to an invasion- and virulence-defective phenotype in Salmonellae.

Two phenotypes believed to contribute to the pathogenesis of Salmonella infections are macrophage survival and invasion of epithelial cells. It was recently observed that the Salmonella macrophage survival factor PagC has significant amino acid similarity to the Yersinia invasion factor Ail. This observation raised the possibilities that macrophage survival is in part determined by the pathway of entry and that PagC confers an entry mechanism that does not trigger the microbicidal activities of the macrophage. Thus, we sought to investigate the role of PagC in invasion by examining (i) the invasion phenotype of pagC mutants and (ii) the invasion phenotype of Escherichia coli carrying pagC. A previously identified invasion-defective TnphoA insertion mutant of Salmonella enteritidis was found to have TnphoA inserted into the signal sequence-encoding region of pagC; the pagC allele from this mutant, SM5T, was designated pagC64. In contrast, Salmonella typhimurium carrying the pagC1 allele (a TnphoA insertion mutation, downstream of the region encoding the signal sequence) was not defective for invasion. Further analysis of these two pagC alleles suggested that the invasion-defective phenotype associated with pagC64 is not due to the loss of PagC function but rather is due to the synthesis of a hybrid PagC-alkaline phosphatase protein that is aberrantly localized, most likely to the inner membrane, and thus may prevent proper localization or function of a factor(s) required for efficient invasion. The observation that pagC did not confer an invasive phenotype to E. coli further suggests that PagC is not an invasion factor. A cloned pagC gene complemented the macrophage survival defect of S. typhimurium pagC1 mutants, but the cloned ail gene did not. Together these results suggest that the structural similarity between PagC and Ail may not extend to a similarity in function. Interestingly, S. enteritidis carrying the pagC64 allele that results in both an invasion defect and a macrophage survival defect was less virulent for mice infected intragastrically or intraperitoneally than was S. enteritidis carrying the pagC1 allele that results only in a macrophage survival defect.

Alkaline Phosphatase↗
PubMed1992

Fatty-acyl esters of retinol (vitamin A) in the liver of the harp seal (Phoca groenlandica), hooded seal (Cystophora cristata), and California sea lion (Zalophus californianus).

The fatty-acid composition of retinyl esters in the livers of two species of phocid seal, the harp seal (Phoca groenlandica, n = 20) and the hooded seal (Cystophora cristata, n = 15), and one species of otariid seal, the California sea lion (Zalophus californianus, n = 6), was determined. Vitamin A ranged in concentration from 4 to 1024 nmol retinol/g liver for the phocids and from 381 to 979 nmol/g liver for the otariids. In most of the livers, retinyl palmitate was not the principal ester, and the palmitate + stearate + oleate trio of retinyl esters represented less than 50% of the total. In all samples, the retinyl esters contained 20:1, 20:4, 20:5, and 22:6 in unusually large amounts. Retinyl esters tended to be richer than whole-liver lipids in 20:5 + 22:6, whereas whole-liver lipids were richer in 18:0 and 18:2. Therefore, the pool of acyl donors used for the esterification of retinol may be distinct from that used for other lipids. Birth-to-weaning changes were seen only in the harp seals. In the pups, the hepatic vitamin-A concentration increased 454%, while the proportion of 18:0 and 20:1 in the retinyl esters rose and that of 14:0 + 16:1 and 20:4 fell. Concomitantly, in their mothers, the proportion of 20:4 increased but that of 16:0 and 18:0 decreased.

Animals↗