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Mass Spectrometry 2017: Heterocyclic aromatic amines and their contribution to the bacterial mutagenicity of the particulate phase of cigarette smoke - Regina Stabbert - University of Cologne.

Regina Stabbert

Since  the  detection  of  substances  with  very  high  bacterial mutagenicity in cooked/broiled meat and fish and their identification  as  heterocyclic  aromatic  amines  (HAAs), this   class of  compounds   has initiated extensive research that is still ongoing. HAAs are formed typically  at  higher  temperatures  (140–165  C)  as  the  result  of Maillard  reactions  involving  creatinine,  free  amino  acids  (espe- cially  tryptophan  and  glutamic  acid),  and  sugars  (Wakabayashi et  al.,  1993).  Special  attention  is  given  in  the  literature  to  the following carboline type of HAAs: MeAaC, AaC, Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2, and the aminoimidazo type of HAAs: IQ, MelQ, MelQx, PhlP. Harman and norharman, although b-carbolines, are not considered as member of the HAA class in most publications as they lack an exocyclic amine group. The exocyclic amine group of HAAs   can   undergo   metabolic   activation   by   N-hydroxylation producing  an  intermediate  (arylnitrenium  ion)  which  has  been implicated  in  general  toxicity  and  DNA  damage  (Turesky  and  Le Marchand, 2011 With the exception of harman and norharman, the mentioned HAAs exhibit a clear in vitro activity inducing reverse mutations in Salmonella typhimurium (Ames assay), morphological transforma- tion in mouse fibroblasts, micronucleus induction in human cells, and DNA strand breaks (Comet Assay) in human cells and  genotoxic  effects  in  vivo  as  DNA  adducts  (Arimoto- Kobayashi et al., 2006; Dingley et al., 2003). Micronuclei formation could be demonstrated for PhlP in mice but not for MelQ and IQ (Durling and Abramsson-Zetterberg, 2005). The carcinogenicity of PhlP,  MelQ,  and  IQ  in  mice  and  rats  in  various  organs,  like  liver, pancreas, colon, mammary gland, and prostate is well established at  doses  around  10 mg/kg/day. Carcinogenicity studies in nonhuman primates with PhlP, MelQ, and IQ could only demonstrate  a  carcinogenic  action  of  IQ  in  the  liver  at  doses  of 10   and   20 mg/kg/day   (Takayama   et   al.,   2008). Differences   in metabolism   between   rodents   and   primates   account   for   the observed  differences  in  the  carcinogenic  effects.

In  humans,  no  occupational  exposures  to  pure  HAAs  have  been reported. However, since the detection of HAAs in food, there are concerns that their presence in food might cause tumors in men.Several epidemiological studies have tried to find an association between the intake of, e.g., cooked meat, cooked fish, or fried potatoes and several  tumor  types,  especially  those  of  the  colon  (WCRF/AICR,1997). These studies are mainly based on questionnaires exploring the diet of the participants. For colorectal adenomas or carcinomas there are more studies that showed an association (although not always  statistically  significant)  than  those  that  gave  a  negative result (Kim et al., 2013; Berlau et al., 2004). Associations between HAAs  and  tumors  at  other  sites  are  in  summary  even   more inconclusive.   Considering   these   uncertainties,   insufficient  evi- dence  exists  to  establish  a  definite  conclusion  on  the  role  of HAAs  in  the  genesis  of  human  tumors. This  conclusion  is  consistent  with  the assessments  of  the  International  Agency  for  Research  on  Cancer that has not listed any of the HAAs as a definite human carcinogen (IARC, 2015); IQ was classified as a ‘probable human carcinogen’(Group  2A)  and  other  assessed  HAAs  (AaC,  Glu-P-1,  Glu-P-2, MeAaC,   MelQ,   MelQx,   Trp-P-1,   Trp-P-2)   as   ‘possible   human carcinogens’  (Group  2B).  Comparing  the  doses  that  gave  rise  to a  distinct  tumor  development  in  rodents  and  monkeys  with  the estimated  daily  oral  intake  of  HAAs  by  humans  shows  that  the estimated  human  exposure  is  more  than  1000  times  lower.  As such, a not yet identified mechanism would be needed to explain a link   between   HAAs   and   human   tumorigenicity (Wakabayashi et al., 1993).Maillard  reactions  are  well-known  to  occur  in  the  burning cigarette  and  as  all  components  necessary  to  form  HAAs  are present in tobacco, it has been suggested that HAAs should also be found  in  cigarette  smoke.  Three  years  after  the  initial  studies  of Sugimura et al. at the National Cancer Center Research Institute in Japan where HAAs in the diet could be identified the  first  HAAs,  AaC  and  MeAaC,  were  identified  and quantified  in  TPM  of  cigarette  smoke . Further studies by several different laboratories  using  different  analytical  methodologies  identified additional HAAs in TPM

Despite some concerns regarding the biological activity of HAAs in TPM, it was only in 1997 that several HAAs were included in a revised  list  of  “[c]arcinogens  in  tobacco  and  cigarette  smoke” issued by Hoffmann and Hoffmann (1997). More recently, the U.S. Food and Drug Administration (FDA) has included 8 HAAs in their list of 93 ‘Harmful and Potentially Harmful Constituents (HPHCs) in tobacco products and tobacco smoke’ (FDA, 2012). A more recent list of 39 priority toxic contents and emissions of tobacco products does not include HAAs (WHO, 2015).

As data on the mutagenicity of HAAs in the context of TPM are scarce   and,   regarding   interactions,   nearly   non-existent,   the research presented here was targeted to corroborate the existing potency  data  on  single  HAAs,  their  occurrence  in  TPM,  their contribution   to   the   overall   mutagenicity   of   TPM,   and   their interactions with TPM or between the HAAs themselves. Hereby, an improved analytical method for the quantification of the HAAs in TPM was applied