metal genotoxicity

Chuck Miller rellim at MAILHOST.TCS.TULANE.EDU
Thu Jul 18 13:35:41 EST 1996

In a previous posting:

>Two hypotheses seems to emerge to explain metal carcinogenicity: 
>induction of oxidative damage and interaction with DNA repair. However, 
>can metals cause promutagenic damage such as DNA strand breaks !!! I 
>am looking for any relevant reference underlying the mechanism.
>Thanks for any help or reference.
>Michel Assad
>E-mail: assad at justine.umontreal.ca 

        There is a good deal of information regarding addtional mechanisms
of metal-induced genotoxicity in addition to mutations resulting from free
radicals and repair inhibition. There is no quick answer to your question,
but perhaps some of the information below will help you get started. 

        Most metals can interact in some way with DNA as you would probably
expect given their opposite charges. Metal compounds such as chromate
(Cr+6, is a great inducer of strand breaks in cells) may be reduced to
species (Cr+3) that can directly interact with DNA. These Cr+3 lesions may
affect DNA by terminating replication or reducing replication fidelity (see
the work of E. Snow and others). Cr+3 can also form DNA-protein and
DNA-amino acid and glutathione crosslinks (see Zhitkovitch, et al. in
Carcinogenesis 16:907 and Biochemistry 35:7275). The crosslinks may be
mutagenic as they are long-lived lesions and may not be well repaired.
Platinum compounds (e.g. cis-diamminedichloroplatinum) are well known
strand breakers and form DNA crosslinks and DNA-protein crosslinks (see
Zwelling, et al. Cancer Res 39:365, Donahue et al, Biochemistry 29:5872).
There is evidence that nickel may act via an epigenetic mechanism involving
heterochomatic regions of the genome (see the work of Costa and coworkers:
Annu. Rev. Pharmacol. Toxicol. 31:321 and Mol. Cell. Biol. 14:851). There
is obviously much more literature (and mechanisms and combinations of
mechanisms) than I have cited here--happy hunting.  

Hope this helps,


Dr. Charles A. Miller,  rellim at mailhost.tcs.tulane.edu 
Bionet.toxicology newsgroup discussion leader
Dept. Environmental Health Sciences 
Rm. 374, Center for Bioenvironmental Research
School of Public Health and Tropical Medicine
Tulane University Medical Center  
1430 Tulane Ave. Box SL29                 
New Orleans, LA 70112               
Ph. 504-585-6942, Fx. 504-585-6939              


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