Nucleotides, adducts

P4501A induction, benzo[a Jpyrene metabolism, and nucleotide adduct formation in fish hepatoma cells effect of preexposure to 3,3/,-4,4/,5-pentachlorobiphenyl. Environ. Toxicol. Chem. 18 474-480, 1999. 

Steenken, S. (1989). Purine bases, nucleosides and nucleotides aqueous solution redox chemistry and transformation reactions of their radical cations and e" and OH adducts. Chem. Rev. 89, 503-520. 

In vitro studies of DNA interactions with the reactive ben-zo[a]pyrene epoxide BPDE indicate that physical binding of BPDE occurs rapidly on a millisecond time scale forming a complex that then reacts much more slowly on a time scale of minutes (17). Several reactive events follow formation of the physical complex. The most favorable reaction is the DNA catalyzed hydrolysis of BPDE to the tetrol, BPT (3,5,6,8,17). At 25°C and pH=7.0, the hydrolysis of BPDE to BPT in DNA is as much as 80 times faster than hydrolysis without DNA (8). Other reactions which follow formation of physical complexes include those involving the nucleotide bases and possibly the phosphodiester backbone. These can lead to DNA strand scission (9 34, 54-56) and to the formation of stable BPDE-DNA adducts. Adduct formation occurs at the exocyclic amino groups on the nucleotide bases and at other sites (1,2,9,17,20, 28,33,34,57,58). The pathway which leads to hydrocarbon adducts covalently bound to the 2-amino group of guanine has been the most widely studied. 

In addition to influencing hydrocarbon metabolite-DNA reactions, the physical binding properties of hydrocarbon metabolites covalently bound to DNA may also be important to carcinogenic activity. The covalent binding of ultimate carcinogens derived from BP and DMBA to DNA produces adducts with tt binding properties similar to those of naturally occurring nucleotides. These adducts... 

Rate constants for reaction of cis-[Pt(NH3)2(H20)Cl]+ with phosphate and with S - and 5/ -nucleotide bases are 4.6xl0-3, 0.48, and 0.16 M-1s-1, respectively, with ring closure rate constants of 0.17 x 10 5 and 2.55x10-5s-1 for subsequent reaction in the latter two cases 220). Kinetic aspects of interactions between DNA and platinum(II) complexes such as [Pt(NH3)3(H20)]2+, ds-[Pt(NH3)2(H20)2]2+, and cis-[Pt(NH3)2(H20)Cl]+, of loss of chloride from Pt-DNA-Cl adducts, and of chelate ring formation of cis-[Pt(NH3)2(H20)(oligonucleotide)]"+ intermediates implicate cis-[Pt(NH3)2(H20)2]2+ rather than cis-[Pt(NH3)2 (H20)C1]+, as usually proposed, as the most important Pt-binder 222). The role of aquation in the overall scheme of platinum(II)/DNA interactions has been reviewed 223), and platinum(II)-nucleotide-DNA interactions have been the subject of molecular modeling investigations 178). 

S. Vepachedu, N. Ya, H. Yagi, J. M. Sayer, D. M. Jerina, Marked Differences in Base Selectivity between DNA and the Free Nucleotides upon Adduct Formation from Bay- and Fjord-Region Diol Epoxides , Chem. Res. Toxicol. 2000, 13, 883 -890. 

In fact, the cyclopropyl group of 26 is strongly electrophilic and reacts readily with amino acids, nucleosides and nucleotides under mild conditions [25 d]. Thus dienone 26 forms covalent adducts with DNA and causes DNA strand breaks DNA is the principal biological target of ptaquiloside 25 [26]. 

DNA adducts most likely reflects increased DNA repair such as nucleotide excision repair and postreplication repair including translesion synthesis, gap filling, and template switching during replication (27,28). 

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