Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes.

1. Methylglyoxal is a reactive alpha-oxoaldehyde and physiological metabolite formed by the fragmentation of triose-phosphates, and by the metabolism of acetone and aminoacetone. 2. Methylglyoxal modifies guanylate residues to form 6,7-dihydro-6,7-dihydroxy-6-methyl-imidazo[2,3-b]purine-9(8)one and N2-(1-carboxyethyl)guanylate residues and induces apoptosis. 3. Methylglyoxal modifies arginine residues in proteins to form N(delta)-(4,5-dihydroxy-4-methylimidazolidin-2-yl) ornithine, N(delta)-(5-hydro-5-methylimidazol-4-on-2-yl)ornithine and N(delta)-(5)methylimidazol-4-on-2-yl)ornithine residues. 4. Methylglyoxal-modified proteins undergo receptor-mediated endocytosis and lysosomal degradation in monocytes and macrophages, and induce cytokine synthesis and secretion. 5. Methylglyoxal is detoxified by the glyoxalase system. Decreased detoxification of methylglyoxal may be induced pharmacologically by glyoxalase I inhibitors which have anti-tumor and anti-malarial activities. 6. The modification of nucleic acids and protein by methylglyoxal is a signal for their degradation and may have a role in the development of diabetic complications, atherosclerosis, the immune response in starvation, aging and oxidative stress.

Pharmacology of methylglyoxal: formation, modification of proteins and nucleic acids, and enzymatic detoxification--a role in pathogenesis and antiproliferative chemotherapy.

Publisher Summary Glutathione transferases with basic isoelectric points have been purified from the human liver, and an acidic form is purified from human erythrocytes. However, this chapter presents a procedure for the preparation of glutathione transferase from human placenta. Enzyme activity during purification is determined spectrophotometrically at 340 nm by measuring the formation of the conjugate of glutathione and l-chloro-2,4-dinitrobenzene. Purification procedure involve the extraction from the human placenta; the supernatant fraction from Step 1 is chromatographed on a column (12.5 x 80 cm) of Sephadex G-25 and the pooled fractions from Step 2 are applied to a column (9 x 13 cm) of DEAE-cellulose equilibrated with l0 mM Tris-HCl at pH 7.8. The pooled effluent from Step 3 is dialyzed overnight against 3 x 10 liter of 10 mM sodium phosphate buffer; then affinity chromatography is carried on S-hexylglutathione coupled to epoxy-activated sepharose 6B and the pooled fractions from Step 5 are charged onto a column of Sephadex G-75 that is equilibrated and eluted with 10 mM sodium phosphate at pH 6.7, containing 0.1 mM dithioerythritol. The active fractions of effluent are pooled.

Glutathione transferase (human placenta).

The glyoxalase system in health and disease.

Methylglyoxal in living organisms: chemistry, biochemistry, toxicology and biological implications.

Studies on the inhibition of glyoxalase I by S-substituted glutathiones.

Glyoxalase inhibitors as potential anticancer agents.

The amount of time spent by nursing personnel in medication-related activities was evaluated in a centralized and a decentralized drug-distribution system. A work-sampling study was used to measure the amount of time spent by nursing personnel in various work activities before and after establishing a satellite pharmacy. Random observations of three nurses and a transcriber were made daily for five-day periods one month before and two months after the satellite pharmacy became operational. The actual number of hours worked by nursing personnel and the patient census during both study periods were also recorded. The lag time for order processing and distribution of initial doses and the accuracy of filling unit dose cassettes were measured in both drug-distribution systems. Nurses' attitudes toward the decentralized system were surveyed three months after implementation of the satellite pharmacy. The percentage of time nurses spent in medication-related activities was significantly less in the decentralized system. Actual hours spent in medication-related activities per patient day were also less in the decentralized system. Lag time for order processing decreased from 55.3 minutes in the centralized system to 15.2 minutes in the decentralized system. The number of unit dose dispensing errors per patient day also decreased after implementing the pharmacy satellite. All nurses surveyed favored the decentralized system. Decentralized drug distribution using a satellite pharmacy was associated with more efficient use of nursing time compared with centralized drug distribution.

Medication-related nursing time in centralized and decentralized drug distribution.

The development of a manual of drug monographs about the handling of antineoplastic agents that complies with the Minnesota Right-to-Know Act is described. The Occupational Safety and Health Administration (OSHA) regulations require manufacturers to provide employees with information about dangerous substances they handle as part of their jobs. OSHA regulations exclude the health-care job sector and drugs, but many states have passed workers' right-to-know acts that include pharmacies. Under the Minnesota Workers' Right-to-Know Act, many antineoplastic drugs are classified as hazardous substances. The Minnesota law applies to all employers, who must provide information and training to all employees who handle these agents. At Midway Hospital in St. Paul, a manual containing information about antineoplastic drugs was developed by the pharmacy department to comply with Minnesota law. The drug monographs were written by pharmacy personnel using information received from drug companies and published articles. The manual was used to teach technicians as well as members of the oncology-unit nursing staff and nursing personnel at a nearby clinic about handling antineoplastic agents. Pharmacy directors in states with right-to-know laws must determine whether the health-care job sector and drugs are covered and, if so, implement policies to teach employees about the handling of these toxic agents.

Wallace B. Wadd

Papers

Studies on the inhibition of glyoxalase I by S-substituted glutathiones.

Glyoxalase inhibitors as potential anticancer agents.

Medication-related nursing time in centralized and decentralized drug distribution.

Complying with workers' right-to-know legislation.