Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • CAA is a carcinogenic metabolite of

    2020-07-30

    CAA is a carcinogenic metabolite of vinyl chloride, forming several different DNA adducts including the cyclic Donepezil HCl adducts 3,N4-ethenocytosine (εC), Donepezil HCl 1,N6-ethenoadenine (εA), N2,3-ethenoguanine (εG), and 1,N2-ethenoguanine (1,N2-εG), with the A and C cyclic adducts the most predominant, and all of which can be mutagenic [[8], [9], [10]]. The εC adduct mostly produces C to A and C to T mutations, whereas εA results in mainly A to C mutations [10,11]. In bacterial systems, εG has miscoding properties and can yield G to A transition mutations [10]. Mutagenic signatures of vinyl chloride exposure have been observed in the oncogenes H-ras and K-ras [12]. The εA and εG adducts can be removed by DNA glycosylases as part of the Base Excision Repair (BER) pathway [13,14]. For example, the εA lesions are excised by the human and E. coli 3-methyladenine-DNA glycosylases and AlkA proteins, respectively [[15], [16], [17]]. E. coli AlkB and its human homologs ABH2 and ABH3 specifically repair base lesions, including the mutagenic exocyclic adducts εC, εA, and 1,N2-εG by using an oxidative dealkylation mechanism known as Direct Repair (DR) [[18], [19], [20], [21]]. SO, the principal metabolite of styrene, is a versatile electrophile that is able to react at various positions on DNA bases [[5], [6], [7],22,23] either through the α- or β-carbon of the epoxide ring, resulting in a diversity of adducts. From studies with nucleosides in vitro, SO has been shown to react at the N7-, N2-, and O6-positions of deoxyguanine (dG), 1- and N6-positions of deoxyadenine (dA), N4-, N3-, and O2-positions of deoxycytosine (dC), and the N3-position of thymine [22,23]. E. coli strains harboring deletions of several DNA repair genes including the SOS-inducible genes recA and uvrA, the adaptive response genes ada, alkB, and alkA, and the 3-methyladenine repair gene tag were treated with SO and other reactive chemicals to evaluate growth [24]. SO caused extreme sensitivity of the E. coli strain lacking DNA damage repair genes relative to the wild-type strain [24]. Induction of the SOS response as a result of E. coli treated with multiple epoxides including SO was also evaluated using the SOS-Chromotest, which revealed that most of the monosubstituted epoxides including SO resulted in SOS induction [25]. E. coli cells have a variety of mechanisms to repair DNA damage, many of which are regulated by the SOS response [[26], [27], [28]]. The SOS response leads to the LexA-, RecA-dependent upregulation of at least 57 genes, including those involved in DNA repair, DNA damage tolerance, and regulation of the cell cycle [1,29]. In addition, the E. coli adaptive response is induced when cells are exposed to DNA-damaging alkylating agents and results in the direct reversal of DNA damage. The Ada protein, a DNA alkyltransferase, directly dealkylates damaged DNA and transfers the alkyl group to itself, leading to the expression of four genes: ada, alkB, alkA, and aidB [30,31]. While human cells lack the LexA-mediated SOS response, most E. coli repair pathways have analogous systems in humans and other organisms [1,32]. Moreover, many of the responses to genotoxic chemicals are conserved in E. coli and humans, so that interesting results with E. coli can, in turn, suggest areas of DNA repair systems in humans for study [33].