ELSEVIER Mutation Research 354 (1996) 147-148

Fundamental and Molecular Mechanisms of Mutagenesis

Current Issues in Mutagenesis and Carcinogenesis, No. 75

Chemical structure: The Cinderella of mutation research

John Ashby Zenecu Central Toxicology Laboratory. Alderley Park, Macclesjield, Cheshire, UK

Received 12 January 1996: accepted 19 January 1996

It is rare for authors of mutagenicity papers to illustrate the chemical structure of the agent they have studied. Given the effort involved in testing chemicals for mutagenicity, it seems worth attempt- ing to relate any activities seen to the structure of the test agent. Such attempts can add value to the obser- vations made by indicating related chemicals that may share similar activities, or by indicating possible mechanisms of mutagenicity/carcinogenicity. Even when such matters are discussed by authors, one usually has to refer back to the Merck Index to find the structure of the chemical whose structure is being discussed. Sections 3 and 4 of Volume 344 of Muta- tion Research can be used to illustrate this problem (for structures see Fig. 1).

In the first paper, Doolittle et al. studied the mutagenicity to Salmonella and CHO cells (SCE) of nicotine (I) and its four major metabolites [cotinine (II), nicotine N’-oxide (III), cotinine N-oxide (IV) and frrrns-3’-hydroxycotinine (V)]. It was concluded that each was non-genotoxic in the assays used, and that they are unlikely to contribute to tobacco-in- duced lung cancer in humans ‘. The structures of these four compounds reveal no obvious centres of

’ Yim and Hee (1995) have subsequently shown that cotinine is an Ddependent genotoxin in a bacterial luminescence assay. Further. these authors suggest that cotinine, perhaps potentiated by

nicotine, may contribute to tobacco associated disease in humans;

i.e.. that cotinine may not be a toxicologically neutral marker of nicotine exposure.

electrophilicity, which adds weight to the negative data reported. Equally, some of the structures alert to the potential for dealkylation/N-nitrosation, yielding compounds such as VI, a known contaminant in cigarette smoke which probably contributes the to- bacco-induced lung cancer.

The second paper, by Hegde and Sujatha, re- ported the micronucleus- and chromosome aberra- tion-inducing properties in the mouse bone marrow of pilocarpine (VII). The chemical structure of pilo- carpine does not alert to electrophilicity, and this adds weight to the suggestion by the authors that it exerts its mutagenic effects either via inhibition of DNA synthesis or via spindle function disturbance. The structure of pilocarpine therefore contributes new information on the structural determinants of indirect mutagenicity. Obviously, more data are needed to discern if the butyrolactone or the imida- zole portions of the molecule (or both) are critical to activity. Nonetheless, a new structure alert to indirect mutagenic potential is created by display of the structure of pilocarpine.

In the same issue, Li et al. probed the origin of the indigenous DNA adducts (I-compounds) pro- duced in the liver of female rats following exposure to a methanol extract of oats. Li et al. concluded that one of the adducts was derived from 4-hydroxynon- enal (VIII), a reactive lipid peroxidation product. Again, when the structure of this compound is seen one realizes that the activity probably derives from either Michael-addition to the double bond. or reac-

0027-5107/96/$15.00 0 1996 Elsevier Science B.V.

PI/ SOO27-5 107(96)00046-2

Nicotine (I) Cotlnlne (II)

Cotinlne- trans-3. N-oxide (IV) hydroxycnfinine (V)

v”7 r;“-‘i

Nicotine- N’-oxide (III)

N-Nitrosonormcotine (VI)

PH ~t,-w- CHzLN

H CH, _CHO

Pllccarpine (VII) 4.Hydroxynonenal (VIII)

Doxorubicin (IX) Moflomycin (X)

Fig. 1. Chemical structures of agents discused in Sections 3 and 4

of volume 333 of Mutation Research.

tion at the aldehyde. Both of these reactions are potentially reversible which means that the adduct levels observed may have under-reported the actual levels of DNA adduction.

The next paper, by Carbonell et al., described temporary variations in chromosomal aberrations in a group of agricultural workers exposed to 43 pesti- cides. The trade names of the 43 agents were listed. but no further attention was paid to the matter. It would perhaps have been inappropriate to illustrate the structure of each of these agents, nonetheless. some of the compounds must have had higher muta- genic potential than others, and the display of those primary suspects would have been valuable. The implication was that nothing beyond the trade name of the agents could contribute to the interpretation of the test data.

Finally, Andrivon et al. noted the reduced muta- genicity of moflomycin (X). a new anthracycline anti-cancer agent related to doxorubicin (XI). These authors illustrated the two chemical structures and discussed the possible chemical reasons for the dif- ferent mutagenicity profiles. They favoured the sugar amino group in doxorubicin being indirectly respon- sible for its mutagenicity, probably via its interaction with the DNA phosphate backbone. That suggestion is stimulating and enables the test data and derived conclusion to be remembered in a chemical context that is almost independent of the DNA-intercalating anthracycline backbone that each chemical shares. One can also note (given access to the structures) that moflomycin contains an apparently non-muta- genic secondary iodo substituent.

Zrz ~~r~lusio~~, it is suggested that the value of mutagenicity test data would be enhanced if the chemical structure of the test agent were to be displayed, and if attempts were made to relate the mutagenic activities observed to the structure of the agent under test. This practice can also alert to instances of mutagenic impurities being responsible for the misclassification of non-mutagens as muta- gens.

References

Andrivon W., Callais F., NafLiger J., Monneret C. and Guillosson

J.J. (1995) A new anthrucycline with potent antileukemic

activity exhibits reduced mutagenicity. Mutation Res.. 313.

135-110.

Carbonell E.. Valbuena A., Xamena N.. Crew A. and Marcos R.

(1995) Temporary variations in chromosomal aberrations in a

group of agricultural workers exposed to pesticides. Mutation

Res., 334. 127-133.

Doolittle D.J.. Winegar R.. Lee C.K.. Caldwell W.S.. Hayes A.W.

and DeBethizy J.D. (1995) The genotoxic potential of nicotine

and its major metabolites. Mutation Res., 344. 95- 102.

Hegde M.J. and Sujatha T.V. (1995) In-viva genotoxicity of the

alkaloid drug pilocarpine nitrate in bone marrow cells and

male germ cell?, ot mice. Mutatwn Rea.. M5. _ 10% 108.

Li D.. Wang M.. Liehr J.G. and Rlrnderath K. (1995) DNA

adducts induced by lipids and lipid peroxidation products:

possible relationshipa to I-compounds. Mutarion Res.. 341.

117-176.

Yim S.H. and Her S.S.Q. (1995) Genotoxicity of nicotine and

cotinine in the bacteria1 luminescence test. Mutation Res.. 335.

175-283.