Environmental and Molecular Mutagenesis - Legacy Tobacco ...

216 1989 EMS Abstracts
Notes
http://legacy.library.ucsf.edu/tid/clb93d00/pdf
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Aztiemely aensi~iVe ~the mutagenio action of 2-nltrofluorene, 1-nitropyrene
and 2-nitronaphthalene . The YG1021 was more sensitive to these chemicals than
TA1538NR(pYG111) gtrjAli~w_hich we previously established, since the YG1021 has
pKM101 . Theae reanlts indicate that the new etrains permit the efficient
detection of mutagenic nitroarenea in the environment .
This work was supported by a Grant-in-Aid from Japan Health Sciences Foundation .
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A SURVEY OF pCTIVITY PROFILES OF A(~TIMUTAGENS/ANTICARCINOGENS .' Waters, M .1, Brady,
A ., Stack, F .2, and Brockman, H .3 ; U .S . Environ . Prot . Agency, Res . Tri . Park, NC ;
2Environ . Hlth . Res . & Testing, RTP, NC ; 3111 . State Univ ., Normal, IL (USA) .
Experimental evidence suggests that chemical mutagenesis and•carcinogenesis are
related phenomena such that identification of causative agents and protection from
exposure might prevent certain human cancers and related diseases . Agents that
inhibit the processes of mutagenesis and carcinogenesis, particularly naturally
occurring agents, might be expected to exert a primary protective effect . This paper
will consider the use of short-term bioassays to identify antimutagenic and
anticarcinogenic substances and to classify them [cf . Mutation Res . 168 (1986) 47-65]
according to the locus of their rotective influence, i .e ., intracellular or
extracellular, and putative mechanismrs) of action . In the extracellular environment,
inhibition of formation or uptake of mutagens and inactivation of promutagenic or
mutagenic species are examples of antimutagenic mechanisms . Intracellularly,
antimutagenic substances have been described as "scavengers" of radicals, "blocking
agents" (involving at least 3 different mechanisms), and "suppressing agents" .
Additional intracellular mechanisms include alterations in DNA repair processes and/or
modification of the genotoxic response to the mutagen/carcinogen . The presentation
format will be based on the genetic activity profile (GAP) methodology developed by
the authors . The GAPs of known mutagens/carcinogens will be presented together wi ht
newly designed profiles for antimutageni/anticarcinogens according to the
classification scheme outlined above . This is an abstract of a proposed
presentation and does not necessarily reflect EPA policy .
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MOLECULAR CHARACTERIZATION OF ERCC2- A HUMAN NUCLEOTIDE EXCISION REPAIR GENE WITH
HOMOLOGY TO THE YEAST RAD3 REPAIR GENE . C.A . Weber, E .P . Salazar, and LH. Thompson, Biomedical
Sciences Division, Lawrence Livermore National Laborabry, Livermore, CA (USA)
The UV-sensltNe Chinese hamster ovary (CHO) cell line mutant UV5 has a defect In the Incision step
of nucleotide excision repair. This same process is defeotive in cells from patients with the cancer-prone
genetic disorder xeroderma pigmentosum (XP) . Genomlc clones of the human ERCC2 (Exdslon gepair
~Qross .QomplemenUng) gene that fully complement the UV5 repair defect in a stable manner have been
isoiated and characterized (Weber et al ., 1988 . Mol. Cell. Biol . 8 :1137-1146) . The genomic clones
were used to Isolate nine ERCC2 clones from the pcD2 human cDNA expression library (obtained from H .
Okayama) . One of the cDNA clones, pER2-14 (inserl size . 2.6 kb), was found to confer transient UVresistance
of an intermediate level to UV5 cells . The nucleolide sequence of pER2•14 and genomic 5'and
3'-flanking regions was determined . Consensus regulatory signals were Identified for a GC box, CAAT
box, TATA promoter, and polyadenylation sNe . Translation of the open reading frame and comparison
with sequenced yeast nucleotide excision repair genes revealed a striking homology between ERCC2 and
RAD3 (-52% Identical ; 760 aa vs . 778 aa) . This comparison, along with examination of the nucleotide
sequence for splice junctions, also revealed that pER2-14 contains part of Intron 1 and produces a
protein that is 24 amino acids short at the amino terminus (738 aa) . This presumably accounts for the
transient nature of the UV-resistance conferred to UV5 alis by pER2-14 . The RAD3 protein has both a
repair and an essential function and has both a single-stranded DNA-dependent ATPase activity and an
ATP-dependent helicase activity . Construction of a cDNA clone with genomic 5'•flankinp sequences that
will produce a full-length protein Is underway . This clone will be used to test for correction of the
repair defect in the CHO UV5 mutant and In the XP complsmentatkan groups. Work performed under the
auspices of the U .S . Department of Energy by LLNL under contract NW-7405-ENG-48 .
MECHANISMS AND PREVENTION OF FORMATION, AND METABOLISM OF FOOD
MUTAGENS/CARCINOGEN 2-AMINO-3-METHYLIMIDAZO[4,5-]QUINOLINE (IQ) .
J .H . Weisburger, R .C . Jones, H .J . Luke, T . Vavrek, American Health
Foundation, Valhalla, NY 10595 USA .
We have postulated that IQ and related imidasoasaarenes, formed
during frying or broiling of meat and fish, may be the genotoxic
carcinogens associated with important types of cancer in humans, like
in the breast, colon or pancreas (Prev . Med . 16 :586,1987) . Their
formation appears to involve Maillard reactions, with creatinine as
critical reactant . In laboratory models involving high temperature
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