The information available on the biological activity of hydrogen sulfide has been examined for present status of critical results pertaining to the toxicity of hydrogen sulfide. This review of the literature is intended as an evaluative report rather than an annotated bibliography of all the source material examined on hydrogen sulfide. The information was selected as it might relate to potential toxic effects of hydrogen sulfide to man and summarized, noting information gaps that may require further investigation. Several recommendations are listed for possible consideration for either toxicological research or additional short- and long-term tests. Two bibliographies have been provided to assist in locating references considered in this report: (1) literature examined but not cited and (2) reference citations. The majority of the references in the first bibliography were considered peripheral information and less appropriate for inclusion in this report.

A Critical Review of the Literature on Hydrogen Sulfide Toxicity

An overview is presented on the molecular aspects of toxicity due to paracetamol (acetaminophen) and structural analogues. The emphasis is on four main topics, that is, bioactivation, detoxication, chemoprevention, and chemoprotection. In addition, some pharmacological and clinical aspects are discussed briefly. A general introduction is presented on the biokinetics, biotransformation, and structural modification of paracetamol. Phase II biotransformation in relation to marked species differences and interorgan transport of metabolites are described in detail, as are bioactivation by cytochrome P450 and peroxidases, two important phase I enzyme families. Hepatotoxicity is described in depth, as it is the most frequent clinical observation after paracetamol-intoxication. In this context, covalent protein binding and oxidative stress are two important initial (Stage I) events highlighted. In addition, the more recently reported nuclear effects are discussed as well as secondary events (Stage II) that spread over the whole liver and may be relevant targets for clinical treatment. The second most frequent clinical observation, renal toxicity, is described with respect to the involvement of prostaglandin synthase, N-deacetylase, cytochrome P450 and glutathione S-transferase. Lastly, mechanism-based developments of chemoprotective agents and progress in the development of structural analogues with an improved therapeutic index are outlined.

Paracetamol (acetaminophen)-induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches.

Various endogenous and exogenous compounds exert cytotoxic effects via oxygen reduction. In general, these are reduced by intracellular enzymes (reductases of various kinds) in one-electron transfer reactions, before they in turn reduce O2 to O2, the superoxide anion radical. Thus, a cycle is formed of O2 uptake at the expense of cellular reducing equivalents, notably NADPH, generating further active oxygen species (figs 1,2). Structures capable of 'redox cycling' include catechols and other quinone compounds, iron chelates, and aromatic nitro compounds. Several anticancer agents, and also some mutagens, operate on this principle, and their toxic effects may be explained by redox cycling. The particular importance of hypoxic conditions for deleterious O2 effects is given by the concomitant flux through reductive as well as oxidative pathways. Toxic effects include membrane damage resulting from peroxidative reactions of polyunsaturated fatty acids (lipid peroxidation), as well as the attack of reactive oxygen species on proteins (enzymes) and nucleic acids; thus O2 metabolism is linked to carcinogenicity and mutagenicity. Lipid peroxidation is also induced by various halogenated compounds such as carbon tetrachloride. Again, hypoxic conditions are particularly critical because, on the one hand, metabolic activation leading to the free radical is enhanced and, on the other hand, oxygen required for the maintenance of lipid peroxidation is still available. - Powerful antioxidant systems of the cell maintain low steady state concentrations of oxygen metabolites, and toxic effects may, in part, also be explained by the constant drain of reducing equivalents resulting from redox cycling.

Toxic drug effects associated with oxygen metabolism: Redox cycling and lipid peroxidation

The plasma pharmacokinetics of the antitumor antibiotic geldanamycin (GM; NSC 122750), a naturally occurring benzoquinoid ansamycin, was characterized in mice and a beagle dog. Concentrations of GM well above 0.1 μg/ml, which was typically effective against neoplastic cell lines responsive to the drug in vitro, were achieved in the plasma of the mice and the dog treated by i.v. injection. However, the systemic duration of the drug was relatively short. Plasma levels decayed below 0.1 μg/ml within 3–4 h after administration of the apparent maximum tolerated doses, which were approximately 20 mg/kg for the mice and 4 mg/kg for the dog. The drug exhibited linear pharmacokinetic behavior within the dose ranges studied. However, there were significant interspecies differences in its disposition. Whereas the mean biological half-life of GM was slightly longer in the mice (77.7 min) than in the dog (57.9 min), its mean residence time in the dog (46.6 min) was more than twofold greater than that observed in the mice (20.7 min). Nevertheless, the drug was cleared from plasma much faster by the dog (49.4 ml/min per kg) than by the mice (30.5 ml/min per kg). These apparent anomalies were principally associated with differences in the relative significance of the terminal phase upon overall drug disposition. The liver appeared to be the principal target organ of acute drug toxicity in the dog. Doses of 2.0 and 4.2 mg/kg both produced elevations in serum levels of the transaminases and other indicators of liver function characteristic of acute hepatic necrosis. Additional effects included symptoms of minor gastrointestinal toxicity and alterations in serum chemistry parameters consistent with less severe nephrotoxicity. Drug-related toxicity appeared to be reversible. In consideration of the potential for acute hepatotoxic reactions to GM, as well as to the other benzoquinoid ansamycins based upon structural analogy, additional pharmacological and therapeutic information is required to ascertain whether these compounds are viable candidates for clinical development.

Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent.

In therapeutic doses paracetamol is a safe analgesic, but in overdosage it can cause severe hepatic necrosis. Following oral administration it is rapidly absorbed from the gastrointestinal tract, its systemic bioavailability being dose-dependent and ranging from 70 to 90%. Its rate of oral absorption is predominantly dependent on the rate of gastric emptying, being delayed by food, propantheline, pethidine and diamorphine and enhanced by metoclopramide. Paracetamol is also well absorbed from the rectum. It distributes rapidly and evenly throughout most tissues and fluids and has a volume of distribution of approximately 0.9L/kg. 10 to 20% of the drug is bound to red blood cells. Paracetamol is extensively metabolised (predominantly in the liver), the major metabolites being the sulphate and glucuronide conjugates. A minor fraction of drug is converted to a highly reactive alkylating metabolite which is inactivated with reduced glutathione and excreted in the urine as cysteine and mercapturic acid conjugates. Large doses of paracetamol (overdoses) cause acute hepatic necrosis as a result of depletion of glutathione and of binding of the excess reactive metabolite to vital cell constituents. This damage can be prevented by the early administration of sulfhydryl compounds such as methionine and N-acetylcysteine. In healthy subjects 85 to 95% of a therapeutic dose is excreted in the urine within 24 hours with about 4, 55, 30, 4 and 4% appearing as unchanged paracetamol and its glucuronide, sulphate, mercapturic acid and cysteine conjugates, respectively. The plasma half-life in such subjects ranges from 1.9 to 2.5 hours and the total body clearance from 4.5 to 5.5ml/kg/min. Age has little effect on the plasma half-life, which is shortened in patients taking anticonvulsants. The plasma half-life is usually normal in patients with mild chronic liver disease, but is prolonged in those with decompensated liver disease.

Clinical Pharmacokinetics of Paracetamol

Evidence for the involvement of N-acetyl-p- quinoneimine in acetaminophen metabolism.

Voltammetry of acetaminophen and its metabolites

Trace Determination of Acetaminophen in Serum

Temperature dependence of electrochemical detection for liquid chromatography

Although liquid column chromatography (LC) had been used as a means of chemical separation for many years prior to 1969, it was not accepted as a method useful for rapid, routine analysis, due to the relatively long times required to achieve resolution. Significant theoretical and technological advances have since been made in this field, and excellent separations can now be achieved within a few minutes using high-efficiency LC column packings. Liquid chromatography offers many advantages over gas-liquid chromatography (GLC) in that no restrictions are placed on the size, volatility, or thermal stability of the sample molecules. In addition, LC offers tremendous flexibility in the choice of mobile and stationary phases such that most sample components can be conveniently resolved using some appropriate combination of mobile and stationary phases.

David J. Miner

Papers

Evidence for the involvement of N-acetyl-p- quinoneimine in acetaminophen metabolism.

Voltammetry of acetaminophen and its metabolites

Trace Determination of Acetaminophen in Serum

Temperature dependence of electrochemical detection for liquid chromatography

Detectors for Trace Organic Analysis by Liquid Chromatography: Principles and Applications