Molecular mechanisms of quinone cytotoxicity.

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.

Three models of free radical-induced cell injury.

(1992). Molecular Aspects of Paracetamol-Induced Hepatotoxicity and its Mechanism-Based Prevention. Drug Metabolism Reviews: Vol. 24, No. 3, pp. 367-407.

Molecular aspects of paracetamol-induced hepatotoxicity and its mechanism-based prevention.

Aerobic organisms by definition require oxygen, and the importance of iron in aerobic respiration has long been recognized, but despite their beneficial roles, these elements can pose a real threat to the organism. During oxygen reduction, reactive species such as O2-. and H2O2 are formed readily. Iron can combine with these species, or with molecular oxygen itself, to generate free radicals which will attack the polyunsaturated fatty acids of membrane lipids. This oxidative deterioration of membrane lipids is known as lipid peroxidation. To protect itself against this form of attack, the organism possesses several types of defense mechanisms. Under normal conditions, these defenses appear to offer adequate protection for cell membranes, but the possibility exists that certain foreign compounds may interfere with or even overwhelm these defenses, and herein could lie a general mechanism of toxicity. This possible cause of toxicity is discussed in relation to other suggested causes.

Ronald J. Gerson

Papers

Oxygen-mediated cell injury in the killing of cultured hepatocytes by acetaminophen

Killing of cultured hepatocytes by the mixed-function oxidation of ethoxycoumarin