Transgenic systems in studies on genotoxicity of alkylating agents: critical lesions, thresholds and defense mechanisms.
Transgenic systems, both cell lines and mice with gain or loss of function, are being used in order to modulate the expression of DNA repair proteins, thus allowing to assess their contribution to the defense against genotoxic mutagens and carcinogens. In this review, questions have been addressed concerning the use of transgenic systems in elucidating critical primary DNA lesions, their conversion into genotoxic endpoints, low-dose effects, and the relative contribution of individual cellular functions in defense. It has been shown that the repair protein alkyltransferase (MGMT) is decisive for protection against methylating and chloroethylating compounds. Protection pertains also to tumor formation, as revealed by the response of MGMT transgenic and knockout mice. Overexpression of genes involved in base excision repair (N-methylpurine-DNA glycosylase, apurinic endonuclease, DNA polymerase beta) is in most cases not beneficial in increasing the protection level, whereas their down-modulation or inactivation increases cellular sensitivity. This indicates that non-repaired base N-alkylation lesions and/or repair intermediates possess genotoxic potential. Modulation of mismatch repair and poly(ADP)ribosyl transferase has also been shown to affect the cellular response to alkylating agents. Furthermore, the role of Fos, Jun and p53 in cellular defense against alkylating mutagens is discussed.
Kaina
B
B
Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, D-55131, Mainz, Germany.
Fritz
G
G
Ochs
K
K
Haas
S
S
Grombacher
T
T
Dosch
J
J
Christmann
M
M
Lund
P
P
Gregel
C M
CM
Becker
K
K
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000633:toxicity*; D009374:Neoplasms, Experimental / Q000139:chemically induced
D000477:Alkylating Agents; D009153:Mutagens