Anders Rudolf Hallberg

Metabolism of N-acetyl-l-cysteine Some structural requirements for the deacetylation and consequences for the oral bioavailability

Rat liver, lung and intestine homogenates deacetylated N-acetyl-L-cysteine. Nearly stoichiometric amounts of L-cysteine were recovered. In rat liver, the enzyme activity was associated with the cytosolic fraction. Liver cytosol was much less active. N-Acetyl-D-cysteine or the disulphide of N-acetyl-L-cysteine were not deacetylated or in other ways consumed in vitro. Isolated, perfused rat liver did not retain or metabolize N-acetyl-L-cysteine to any measurable extent during single-pass experiments. N-Acetyl-L-cysteine or N-acetyl-D-cysteine were injected into a ligated segment of rat intestine in situ. After 1 hr 2% of the L-isomer and 35% of the D-isomer remained in the intestinal lumen. Systemic plasma levels were less than 3 microM of the L-form and congruent to 40 microM of the D-form. We conclude that deacetylation in the intestinal mucosa and possibly in the intestinal lumen is the major factor determining the low oral bioavailability of N-acetyl-L-cysteine. The deacetylation is discussed on the basis of the subcellular localization and the structural requirement of the reaction.

Glutathione peroxidase-like activity of diaryl tellurides.

Abstract 4,4′-Disubstituted dirayl tellurides showed glutathione peroxidase-like catalysis of the reduction of hydroperoxides by glutathione. The most potent compound, bis(4-aminophenyl) telluride, demonstrated 348%, 530%, 995% and 900% of the catalytic efficacy of Ebselen for the glutathione dependent reduction of H 2 O 2 , t-butyl hydroperoxide, cumene hydroperoxide and linoleic acid hydroperoxide, respectively.

Advances in the development of pharmaceutical antioxidants

Publisher Summary This chapter attempts to narrow the gap where antioxidant pharmacology meets with organic chemistry. It is intended to serve as a reference to substances that have been described, designed, or developed as therapeutically relevant antioxidants. It is obvious that the present contribution cannot cover more than a limited number of examples of antioxidants from the large variety of structural classes that have been studied as possible drug candidates. For this purpose, it most fruitful to cover compounds that have emerged from in vitro experimentation and structure–activity studies. The chapter discusses antioxidant effects in molecular and structural terms. The synthetic compounds have been classified chemically, rather than by therapeutic area, as the latter, in most instances, is a matter of the preference of the researchers rather than inherent properties of the substances. Some ranges regarding dose or concentration have been included to indicate the approximate potencies of compounds, especially when standard in vitro assays have been utilized. The enzyme systems that are devoted to detoxification of reactive and potentially pathological oxygen metabolites have also been thoroughly treated by others, and will be mentioned to provide a basis for the discussion of synthetic enzyme mimics. The chapter attempts to present the various conceivable approaches that are at hand for attenuating oxidative tissue injury and the harmful effects that are ascribed to free radicals.

Antioxidant activity of some diarylselenides in biological systems

The selenoorganic compounds di(4-aminophenyl)selenide (10) and 4-nitro-4-amino-diphenylselenide (36) were shown to inhibit lipid peroxidation in ADP/Fe2+/ascorbate-treated microsomes and tert-butylhydroperoxide-treated hepatocytes with IC50s of 3 and 10 microM, and 14 and 10 microM, respectively. In the former system, these inhibition constants compare favourably with those of Ebselen and classical antioxidants such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). In the cell system, these selenium compounds were equipotent with BHA but more potent than Ebselen and its analogues. The diamino compound (10) was also an effective inhibitor of lipid peroxidation initiated by diquat redox cycling in hepatocytes, again being equipotent with BHA but more potent than Ebselen and its analogues, which actually stimulated lipid peroxidation in this test system. Manipulation of the amino functions of (10) and (36) by alkylation or acylation altered the antioxidant capacity. Optimal activity in this series was achieved by N-ethylation or N-isobutylation of (10). This produced antioxidants having IC50s below 1 microM in the microsome system, 3-13 microM in the tert-butylhydroperoxide system, and being 100% effective in the diquat model at 50 microM. On the other hand, acylation or alkylation of the amino groups with long chain acyl or alkyl groups reduced the efficacy of the structures below that of the parent diamine. As with other antioxidant compounds, several of the chalcogenides were relatively selective inhibitors of monocyte 5-lipoxygenase-dependent secretion of LTB4 as compared to their effect on cyclooxygenase-dependent secretion of PGE2 (for example compound 42 had IC50s of 0.6 microM and 10 microM, respectively). No correlation was observed between the redox-properties of the chalcogenides and their respective abilities to inhibit these enzymes.