Showing papers by "Richard Bucala published in 1985"

Modification of DNA by glucose 6-phosphate induces DNA rearrangements in an Escherichia coli plasmid.

Abstract: Reducing sugars such as glucose or glucose 6-phosphate (Glc-6-P) have been shown previously to modify the amino groups of nucleotides and single-stranded DNA. We have examined the mutagenic effect of Glc-6-P-induced lesions in the double-stranded DNA plasmid pBR322. Seventeen mutants of the Ampr Tets phenotype were isolated from plasmid preparations whose transforming capacity had been decreased by incubation with Glc-6-P. A number of the mutant plasmids were found to have undergone gross DNA alterations, including insertions and deletions, as well as the development of multiple species originating from a single cell. The ability of an endogenous reducing sugar to induce extensive DNA rearrangements suggests that these lesions may be significant contributors to cellular mutation.

Determination of 16 alpha-hydroxyestrone by radioimmunoassay in systemic lupus erythematosus.

Abstract: A radioimmunoassay for the feminizing metabolite 16 alpha-hydroxyestrone was applied to a variety of sera from healthy volunteers, patients with active or inactive systemic lupus erythematosus (SLE), and patients with other rheumatic diseases. A significant increase in this metabolite was detected in patients with SLE, especially those with active disease, compared with normal controls (P less than 0.001). SLE patients were categorized as having either active or inactive disease by clinical and laboratory criteria. Many patients who had clinically and serologically active disease were found to have normal levels of this estrogenic metabolite, and several explanations for these differences are explored in this report. Despite a poor correlation of hormone levels with age, antibody levels, or complement levels in patients with SLE, those patients with the highest levels of hormone were among those whose disease was clinically most active.

Increased Levels of 16α-Hydroxyestrone-Modified Proteins in Pregnancy and in Systemic Lupus Erythematosus

Abstract: The ketolic estrogen 16α-hydroxyestrone (16αOHE) reacts with lysine residues, forming stable covalent adducts with proteins. To determine the extent of protein modification by 16αOHE in vivo, we measured the level of 16αOHElysine present within proteins of varying half-lives obtained from normal subjects, patients with systemic lupus erythematosus (SLE), and pregnant women. The latter groups have higher than normal levels of plasma 16αOHE. The proteins analyzed were membrane proteins of the red cell and the lymphocyte and basement membrane proteins of the glomerulus. We report that elevated levels of plasma 16αOHE led to increased formation of 16αOHE-protein adducts and that the level of these adducts increases with the half-life of the protein. In the case of erythrocyte membrane proteins, pregnant women and women with SLE had significantly higher mean levels of 16αOHE-lysine than normal women (normal, 5.2 pmol 16αOHE-lysine/mmol leucine; SLE, 15.7; pregnant, 24.9). A similar elevation in the modificatio...

Non-enzymatic modification of proteins by steroids: pathological implications for autoimmunity and glucocorticoid toxicity.

Abstract: Certain steroids can react with proteins to form stable, covalent addition products. 16α-hydroxyestrone and the glucocorticoids, for example, contain ketol moieties which permit them to react non-enzymatically with proteins by forming Schiffbase rearrangement products with lysine residues. The oral contraceptive agent, 17α-ethinylestradiol, can add to proteins after being enzymatically activated by microsomal oxidation. Elevated plasma levels of these steroids result in an increased amount of protein modification in vivo. Recent investigations have linked the occurrence of steroid-modified proteins with pathological sequelae associated with high steroid levels.

Role of Sex Steroids in Systemic Lupus Erythematosus (SLE)

Abstract: Sex Steroids are important to the pathogenesis of SLE, a disease which affects females in preference to males (13:1). Abnormalities of estrogen metabolism and androgen metabolism in the human have been described. Increased 16 hydroxylation of estrone has been found in males and females, whereas increased oxidation of testosterone (C-17) has been found only in females with the disease. Females with SLE have low plasma androgens. Patients with active disease have the lowest levels. The compound 16 alpha hydroxyestrone, a unique and potent estrogen, has been shown to bind covalently to plasma proteins and cell membranes. This compound is a product of 16 hydroxylation, and may be important to the pathogenesis of SLE.