Metabolic Activation of Toxins: Tissue-specific Expression and Metabolism in Target Organs
Olavi Pelkonen and Hannu Raunio
Department of Pharmacology and Toxicology, University of Oulu,
Oulu, Finland
Abstract
Cytochrome P450 (CYP) enzymes catalyze the generation of reactive species capable of binding with cellular macromolecules, leading to acute and delayed toxicity. Since individual CYP forms differ markedly in their substrate preferences and regulation, the expression profiles of CYP in various cell types are important determinants in tissue-specific toxicity. The highest concentrations of most forms of CYP are found in liver, but they are also present in many extrahepatic organs. Liver is also a target organ in which CYP-mediated activation and toxic outcome have been most convincingly linked. Prime examples are paracetamol-induced hepatotoxicity and aflatoxin B1-associated hepatic cancer. In contrast to liver, most extrahepatic tissues are composed of multiple cell types, which make experimental approaches difficult. Also the low abundance of individual forms is a challenge in the study of extrahepatic CYP-related toxicity. Recent years have witnessed the emergence of molecular biological techniques, e.g., reverse transcriptase-polymerase chain reactions, which facilitate the study of low abundant CYP forms in human tissues. Nevertheless, in the end we need definite information on the expression of activity, and for this purpose enzyme-specific substrates, reactions, and inhibitors and other methods to detect proteins and associated activities are needed. In humans, it is important to measure activities of specific enzymes in vivo. For this purpose, two approaches are currently available. Metabolism and/or elimination of enzyme-specific drugs can be employed. In cases in which genetic background determines the presence or absence of a specific enzyme, phenotyping and genotyping tests can be devised, e.g., for CYP2D6 (debrisoquine hydroxylation) polymorphism. -- Environ Health Perspect 105(Suppl 4):767-774 (1997)
Key words: xenobiotic metabolism, metabolic activation, cytochrome P450, CYP, tissue-specific expression, polymorphism
This paper was prepared as background for the Workshop on Susceptibility to Environmental Hazards convened by the Scientific Group on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC) held 17-22 March 1996 in Espoo, Finland. Manuscript received at EHP 5 November 1996; accepted at EHP 18 November 1996.
The research in the authors' laboratory has been supported by The Academy of Finland (contracts 1051029 and 29456). This article was written within the framework of the Action COST B1.
Address correspondence to Dr. O. Pelkonen, Department of Pharmacology and Toxicology, University of Oulu, FIN-90220 Oulu, Finland. Telephone: (358) 81-5375011. Fax: (358) 81-5375247. E-mail: olavi.pelkonen@oulu.fi
Abbreviations used: AHH, aryl hydrocarbon (benzo[a]pyrene) hydroxylase; CYP, cytochrome P450; MAO-B, monoamine oxidase B; MTPT, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPP+, 1-methyl-4-phenyl-pyridinium ion; PAH, polycyclic aromatic hydrocarbon; RFLP, restriction fragment length polymorphism; RT-PCR, reverse transcriptase-polymerase chain reaction.
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Last Update: June 13, 1997