Antonietta Martelli¹, Giovanni Brambilla¹

1Department of Internal Medicine, Division of Clinical Pharmacology and Toxicology, University of Genoa, Viale Benedetto XV, 2, I-16132 Genoa, Italy

TABLE OF CONTENTS

1. Abstract

2. Introduction

3. Drug-nitrite interaction products

4. Genotoxic and carcinogenic effects of drug-nitrite interaction products

5. Discussion and Conclusions

6. References

1. ABSTRACT

This review provides information on arylamine drugs which have been tested for the formation of N-nitroso compounds (NOC) by reacting with nitrite, and on the genotoxic-carcinogenic effects of their nitrosation products. In an extensive search we have found that 109 arylamine drugs were examined for their ability to react with nitrite, and 105 of them (96.3%) were found to form NOC or in some cases other reactive species. Moreover, 78 arylamine drugs were examined in short-term genotoxicity tests and/or in long-term carcinogenicity assays, either in combination with nitrite or using their nitrosation product; 67 of them (85.9%) have been found to give at least one positive response. Only a small fraction, the 19.1% of theoretically nitrosatable arylamine drugs, has been examined for the possible formation of genotoxic-carcinogenic NOC, guidelines for genotoxicity testing of pharmaceuticals do not indicate the need of appropriate tests, and patients are not informed that the drug-nitrite interaction and the consequent risk can be reduced to a large extent by consuming the nitrosatable drug with ascorbic acid.

2. INTRODUCTION

N-nitroso compounds (NOC) are known for their capability of inducing the development of tumours in a large number of animal species (1). This suggests that they may also be carcinogenic to humans, even if a causal relationship between exposure to NOC and human cancer has not yet been rigorously established. In this respect it should be considered that to demonstrate in the human population such a relationship is difficult due to the exposure to low levels of NOC, to the limited sensitivity of epidemiological instruments, and to the lack of a truly unexposed population that can be used as control. Human exposure to NOC can be the consequence either to intake of preformed NOC or to endogenous formation of NOC in vivo from nitrosatable precursors and nitrosating agents. The chemistry of NOC formation has been previously extensively described (2,3). In brief, the formation of NOC requires the presence of a nitrosatable compound, acid and inorganic nitrite. The main site of the NOC endogenous synthesis is undoubtedly the stomach where after consumption of nitrite-rich meals the concentration of nitrite can reach 100-300 micromol/liter.

As reviewed by Mirvish (2), NOC can be also formed from aryl, diaryl and alkylaryl amines. As pharmacologists we are primarily concerned with the genotoxic-carcinogenic risk possibly linked to NOC generated in vivo by the nitrosation of pharmaceutical preparations. In the 2007 edition of Martindale -The Complete Drug Reference (4) are listed 570 aryl- , diaryl-, and alkylaryl-amine drugs. The aim of this review is to list which of these drugs have been found to form NOC by reacting with nitrite, and to indicate the genotoxic and carcinogenic effects of their nitrosation products.

3. DRUG-NITRITE INTERACTION PRODUCTS

Table 1 lists 109 arylamine drugs, representing a wide variety of chemical structures and therapeutic families, the large majority of which (96.3%) by reacting with nitrite have been found to form NOC or, in a few cases, other reactive species. For each drug is indicated the yield(s) of NOC as % of the theoretical one and, when it was identified, the NOC formed. Since the nitrosation of many drugs was investigated in various studies in different reaction conditions, for these drugs is indicated in the table the lowest and highest yield obtained in each of these studies. For each study the corresponding reference is indicated in parentheses. Because the yield of NOC depends not only on the chemical structure of the drug but also on the drug-nitrite molar ratio, pH, temperature and reaction time, the wide range of yields obtained for the same drug in different reaction conditions is not surprising. For most drugs the lowest yield was obtained in simulated in vivo conditions, and the highest yield when the reaction was carried out according to the nitrosation assay procedure of the WHO (5) or in even more favourable conditions. The WHO nitrosation assay procedure (NAP test) must conform to the following criteria: concentration of drug, 10 mM; concentration of nitrite, 40 mM; reaction temperature, 37�C; pH, 3-4; reaction times, 1 and 4 h. Obviously, the results so obtained do not allow a quantitative prediction of the nitrosation rate and yield in the stomach of a patient treated with a therapeutic dose of a nitrosatable drug that depend on substrates, catalysts and inhibitors, and are influenced by the stomach content, pH and several other factors.

4. GENOTOXIC AND CARCINOGENIC EFFECTS OF DRUG-NITRITE
INTERACTION PRODUCTS

Table 2 lists the results of genotoxicity and/or carcinogenicity assays carried out with the arylamine drugs which have been found to form by reacting with nitrite a NOC or in some cases a different type of reactive species. In vitro assays were performed by treatment either with the nitrosation reaction mixture or directly with the NOC formed by the specific drug; in in vivo assays either the treatment with the drug and nitrite or the administration of the NOC formed by the drug were employed. Of the 78 drugs listed in Table 2, 66 formed a NOC that tested positive in at least one, and often in more than one, genotoxicity assay. Only 10 were tested for carcinogenicity, and 6 of them gave at least one positive response. However, it should be considered that the nitrosation of 28 drugs listed in Table 1 gave rise to one of the following well known carcinogenic NOC described in IARC Monographs (101) : N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosmorpholine, N-nitrosopiperidine, N-nitrosodipropylamine, or N-nitrosopyrrolidine.

5. DISCUSSION AND CONCLUSIONS

The large majority of NOC have been found to be genotoxic and carcinogenic; four NOC have been classified by the International Agency for Research on Cancer (IARC) as probably and other 15 as possibly carcinogenic to humans (102). In our extensive search we have found that 105 arylamine drugs have been found to form NOC or other reactive species (Table 1) and we cannot exclude that additional published and unpublished results exist. Certainly the number of theoretically nitrosatable arylamine drugs that have not been tested for their possible nitrosation to genotoxic-carcinogenic derivatives is very high.

Conditions suitable to nitrosation reactions are present in the human organism, mainly in the stomach where, after consumption of nitrite-rich meals, the concentration of nitrite can reach 100-300 micromol/liter. One of the major factors regulating the formation of NOC in the gastric environment is the concentration of nitrosating agents (N₂O₃, NO+, and ON-NCS) which are derived from nitrite ion (NO₂-) or nitrous acid (HNO₂). Gastric nitrite can be ingested directly with food or water, but most of it arises from enzymatic reduction of nitrate in saliva or gastric juice. Two distinct mechanisms of endogenous formation of NOC have been identified. The first, a direct chemical reaction between secondary amino compounds and nitrite, is strongly pH dependent and does not proceed rapidly at neutral pH. The second mechanism depends on direct bacterial catalysis of N-nitrosation and proceeds much more rapidly at neutral pH than the chemical reaction.

In spite of these possibilities, guidelines for genotoxicity testing of pharmaceuticals (103) do not indicate the need of performing adequate tests in order to assess whether a nitrosatable drug may undergo endogenous nitrosation to a genotoxic-carcinogenic NOC. The amounts of NOC formed in the human stomach are presumably very small, but it cannot be excluded that some arylamine drugs might yield a not negligible amount of genotoxic reaction product(s). According to Preussmann (104), the continuous exposure to a NOC leads to a linear dose-effect and dose-time relationship which do not indicate deviations from linearity at low doses; consequently there would be no indication of a no-effect level, and small single doses should be additive. In comparison to the dietary exposure to nitrosatable amines, that is normally below 100 mg/day, several nitrosatable arylamine drugs are used therapeutically at doses higher than 100 mg/day, and some non-prescription arylamine drugs at much higher doses, e.g. acetaminophen that can reach the daily dose of 4 g. Obviously the genotoxic-carcinogenic risk related to the endogenous drug nitrosation should be compared with the therapeutic benefit, but it should be taken into account that the drug-nitrite interaction can be to a large extent reduced by administering the nitrosatable drug with ascorbic acid that rapidly reacts with nitrite to give nitric oxide and dihydroascorbic acid.

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Key Words: Arylamine drugs, NO-derivatives, Genotoxic-carcinogenic activity, Review