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Mutation Research, 33 (1975) 25--26 © Elsevier Scientific Publishing Company, Amsterdam -- Printed in The Netherlands
METABOLIC ACTIVATION AND REACTIVITY OF CHEMICAL CARCINOGENS
JAMES A. MILLER and ELIZABETH C. MILLER
McArdle Laboratory for Cancer Research, University of Wisconsin Medical Center, Madison, Wisconsin 53706 (U.S.A.) (Received July 10th, 1975) (Accepted August 25th, 1975)
Chemical carcinogens, including those known to be active in man, consist primarily of a large group of synthetic and naturally occurring organic compounds of very diverse structures and with various species and tissue selectivities. Only recently has a c o m m o n basis been recognized for the chemical and biological activities of these agents. Considerable evidence now indicates that the ultimate reactive and carcinogenic forms of most, if not all, chemical carcinogens are strong electrophilic (electron-deficient) reactants. The majority of chemical carcinogens are precarcinogens that require enzymatic activation in vivo into these reactive ultimate carcinogens. Similarly, many chemical carcinogens are reactive electrophiles per se (alkylating agents and a few acylating agents and other electrophiles). The reactions of the ultimate electrophilic forms of chemical carcinogens with nucleophilic (electron-rich) atoms in cellular macromolecules account for the formation of the covalent nucleic acid- and protein-bound forms of these agents long noted in vivo. Studies on these covalently b o u n d carcinogen residues indicate that many nucleophilic atoms in these macromolecules are targets of chemical carcinogens in vivo. Likewise, some of the more complex chemical carcinogens have been found to be metabolized to more than one electrophilic form. Since the conversion of normal cells to malignant cells appears to be irreversible and is heritable the critical targets in chemical carcinogenesis appear to be critical informational macromolecules such as nucleic acids, or proteins, or both that are involved in the control of growth. At present b o t h genetic and epigenetic mechanisms, with and without the involvement of carcinogenic viral information, must be considered as possible means by which ultimate chemical carcinogens induce neoplasia. Carcinogenesis and mutagenesis are grossly alike in that each process leads to heritable changes in p h e n o t y p e although the time scales in which these processes operate may differ widely. Most chemical carcinogens and most chemical mutagens also have much in c o m m o n since their active forms in vivo are electrophilic reactants and attack the same macromolecules. However, while the criti-
26
cal cellular target of chemical mutagens has been shown to be DNA, the critical cellular targets of chemical carcinogens have not been defined unequivocally. Thus, no gross correlation, however good, between the carcinogenicities and mutagenicities of chemicals can establish mutagenic events as components of chemical carcinogenic processes since chemical carcinogens react with macromolecules other than DNA. However, while there may or may not be a causal relationship of mutagenesis with carcinogenesis, the common electronic nature of the active forms of most chemical carcinogens and mutagens and the common mutagenicity of ultimate chemical carcinogens indicate that a strong formal relationship exists. Hence, most, and possibly all, chemical carcinogens are potential mutagens and most, but possibly not all, chemical mutagens are potential carcinogens. The possible exceptions are the small groups of base analog and simple frame-shift mutagens. Neither of these groups is mutagenic through electrophilic forms and neither group appears to exhibit much carcinogenic activity. However, these compounds have not yet received adequate testing for carcinogenicity. In any event, the formal relationship between the carcinogenicity and mutagenicity o f chemicals appears strong enough to be the basis for the use of mutagenicity test systems in the detection of potential chemical carcinogens among the many man-made and naturally occurring compounds in our environment. Since most chemical carcinogens require metabolic activation these test systems must include activation enzymes. Extensive comparison of results in these mammalian tissue-mediated mutagenicity test systems with the results of conventional tests for carcinogenicity will be required to establish the utility of the former systems in the detection of potential carcinogenicity of chemicals. References 1 Miller, J . A . , C a r c i n o g e n e s i s b y c h e m i c a l s : a n o v e r v i e w - - G . H . A . C l o w e s M e m o r i a l L e c t u r e , C a n c e r Res. 30 (1970) 559--576. 2 Miller, J . A . , a n d E.C. Miller, C h e m i c a l carcinogenesis: mechanisms a n d a p p r o a c h e s t o its c o n t r o l , J. Natl. C a n c e r Inst., 4 7 ( 1 9 7 1 ) V - - X I V . 3 Miller, E.C., a n d J . A . Miller, T h e m u t a g e n i c i t y o f chemical carcinogens: c o r r e l a t i o n s , p r o b l e m s , a n d interpretations, in A. H o i l a e n d e r ( E d . ) , Chemical Mutagens: P r i n c i p l e s a n d M e t h o d s f o r T h e i r D e t e c t i o n , Vol. 1, P l e n u m , N e w Y o r k , 1 9 7 1 , p p . 8 3 - - 1 1 9 . 4 Miller, E.C., a n d J . A . Miller, B i o c h e m i c a l m e c h a n i s m s o f c a r c i n o g e n e s i s , in H. B u s c h ( E d . ) T h e M o l e c u lar B i o l o g y o f C a n c e r , A c a d e m i c Press, N e w Y o r k , 1 9 7 4 , p p . 3 7 7 - - 4 0 2 .
Mutation Research, 33 (1975) 25--26 © Elsevier Scientific Publishing Company, Amsterdam -- Printed in The Netherlands
METABOLIC ACTIVATION AND REACTIVITY OF CHEMICAL CARCINOGENS
JAMES A. MILLER and ELIZABETH C. MILLER
McArdle Laboratory for Cancer Research, University of Wisconsin Medical Center, Madison, Wisconsin 53706 (U.S.A.) (Received July 10th, 1975) (Accepted August 25th, 1975)
Chemical carcinogens, including those known to be active in man, consist primarily of a large group of synthetic and naturally occurring organic compounds of very diverse structures and with various species and tissue selectivities. Only recently has a c o m m o n basis been recognized for the chemical and biological activities of these agents. Considerable evidence now indicates that the ultimate reactive and carcinogenic forms of most, if not all, chemical carcinogens are strong electrophilic (electron-deficient) reactants. The majority of chemical carcinogens are precarcinogens that require enzymatic activation in vivo into these reactive ultimate carcinogens. Similarly, many chemical carcinogens are reactive electrophiles per se (alkylating agents and a few acylating agents and other electrophiles). The reactions of the ultimate electrophilic forms of chemical carcinogens with nucleophilic (electron-rich) atoms in cellular macromolecules account for the formation of the covalent nucleic acid- and protein-bound forms of these agents long noted in vivo. Studies on these covalently b o u n d carcinogen residues indicate that many nucleophilic atoms in these macromolecules are targets of chemical carcinogens in vivo. Likewise, some of the more complex chemical carcinogens have been found to be metabolized to more than one electrophilic form. Since the conversion of normal cells to malignant cells appears to be irreversible and is heritable the critical targets in chemical carcinogenesis appear to be critical informational macromolecules such as nucleic acids, or proteins, or both that are involved in the control of growth. At present b o t h genetic and epigenetic mechanisms, with and without the involvement of carcinogenic viral information, must be considered as possible means by which ultimate chemical carcinogens induce neoplasia. Carcinogenesis and mutagenesis are grossly alike in that each process leads to heritable changes in p h e n o t y p e although the time scales in which these processes operate may differ widely. Most chemical carcinogens and most chemical mutagens also have much in c o m m o n since their active forms in vivo are electrophilic reactants and attack the same macromolecules. However, while the criti-
26
cal cellular target of chemical mutagens has been shown to be DNA, the critical cellular targets of chemical carcinogens have not been defined unequivocally. Thus, no gross correlation, however good, between the carcinogenicities and mutagenicities of chemicals can establish mutagenic events as components of chemical carcinogenic processes since chemical carcinogens react with macromolecules other than DNA. However, while there may or may not be a causal relationship of mutagenesis with carcinogenesis, the common electronic nature of the active forms of most chemical carcinogens and mutagens and the common mutagenicity of ultimate chemical carcinogens indicate that a strong formal relationship exists. Hence, most, and possibly all, chemical carcinogens are potential mutagens and most, but possibly not all, chemical mutagens are potential carcinogens. The possible exceptions are the small groups of base analog and simple frame-shift mutagens. Neither of these groups is mutagenic through electrophilic forms and neither group appears to exhibit much carcinogenic activity. However, these compounds have not yet received adequate testing for carcinogenicity. In any event, the formal relationship between the carcinogenicity and mutagenicity o f chemicals appears strong enough to be the basis for the use of mutagenicity test systems in the detection of potential chemical carcinogens among the many man-made and naturally occurring compounds in our environment. Since most chemical carcinogens require metabolic activation these test systems must include activation enzymes. Extensive comparison of results in these mammalian tissue-mediated mutagenicity test systems with the results of conventional tests for carcinogenicity will be required to establish the utility of the former systems in the detection of potential carcinogenicity of chemicals. References 1 Miller, J . A . , C a r c i n o g e n e s i s b y c h e m i c a l s : a n o v e r v i e w - - G . H . A . C l o w e s M e m o r i a l L e c t u r e , C a n c e r Res. 30 (1970) 559--576. 2 Miller, J . A . , a n d E.C. Miller, C h e m i c a l carcinogenesis: mechanisms a n d a p p r o a c h e s t o its c o n t r o l , J. Natl. C a n c e r Inst., 4 7 ( 1 9 7 1 ) V - - X I V . 3 Miller, E.C., a n d J . A . Miller, T h e m u t a g e n i c i t y o f chemical carcinogens: c o r r e l a t i o n s , p r o b l e m s , a n d interpretations, in A. H o i l a e n d e r ( E d . ) , Chemical Mutagens: P r i n c i p l e s a n d M e t h o d s f o r T h e i r D e t e c t i o n , Vol. 1, P l e n u m , N e w Y o r k , 1 9 7 1 , p p . 8 3 - - 1 1 9 . 4 Miller, E.C., a n d J . A . Miller, B i o c h e m i c a l m e c h a n i s m s o f c a r c i n o g e n e s i s , in H. B u s c h ( E d . ) T h e M o l e c u lar B i o l o g y o f C a n c e r , A c a d e m i c Press, N e w Y o r k , 1 9 7 4 , p p . 3 7 7 - - 4 0 2 .
