Tissue specificities of tumor induction by aromatic amines

Ching Yung Wang¹, Charles Miller King²

1Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210 and ²Department of Chemical Carcinogenesis, Michigan Cancer Foundation, Detroit, Michigan 48201

TABLE OF CONTENTS

1. Abstract

2. Introduction

3. What is required for the induction of tumors by chemicals?

3.1. Modification of protein by AA

3.2. Modification of nucleic acids by AA

3.3. Reactive nitrenium derivatives

3.3.1. Formation by cytosolic acyltransferases

3.3.2. Formation by microsomal acyltransferases

3.3.3. Formation by cytosolic sulfotransferase

3.3.4. Circumventing the need for enzymatic N-oxidation

3.4. Activation by cyclooxygenases

3.5. What are the criteria for the production of tumors in humans by AA?

3.5.1. Distribution of compounds that are precursors suitable for metabolic activation by the target tissues

3.5.2. Metabolic activation

3.5.3. Fate of modified nucleic acid

3.5.4. Amplification of altered DNA templates

3.5.5. Epidemiological considerations

4. Summary and perspectives

5. Acknowledgements

6. References

1. ABSTRACT

Certain aryl compounds that have nitrogen substitutions on their ring structures are, following metabolic conversion to reactive derivatives, able to elicit toxic responses by virtue of their modifications of protein and nucleic acid. This group of compounds is often referred to as aromatic amines (AA), although from a structural perspective, compounds that can be converted metabolically to crucial AA derivatives are also capable of producing the same adverse biological effects. These effects include cellular death, mutagenic events and tumor induction. Importantly, in humans, AA can induce tumors in the urinary tract, and possibly other tissues. This contribution addresses the mechanisms by which AA are likely to produce these carcinogenic consequences.