Correlation of carcinogenic potency with mouse-skin 32P-postlabeling and muta-Rmouse lac Z- mutation data for DMBA and its K-region sulphur isostere: comparison with activities observed in standard genotoxicity assays.
The genotoxicities in vitro and in vivo of the mouse-skin carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) have been compared with those of its weakly carcinogenic 4,5-sulphur analogue, 6,11-dimethylbenzo[b]naphtho-[2,3-d]thiophene (S-DMBA). The only datasets that correlated with the relative carcinogenicity of these agents to the skin were those conducted using topically exposed mouse skin. Thus, both chemicals induced lacZ- mutations in the skin of lacZ+ transgenic mice, and both produced DNA adducts on mouse-skin DNA as assessed using the 32P-postlabeling technique. In each case, DMBA gave a stronger response than did S-DMBA. In contrast to these responses, only DMBA was active in the mouse bone-marrow micronucleus assay and in the C3H10T1/2 in vitro cell transformation assay. Both chemicals were mutagenic to Salmonella and of approximately equal potency. The molecular geometry of DMBA and S-DMBA are compared, and divergent CASE predictions of activity in the Salmonella assay and skin-painting bioassay are discussed. The importance of conducting predictive genotoxicity assays in systems close to those in which carcinogenicity is to be assessed is emphasized by these data.
Ashby
J
J
ZENECA Central Toxicology Laboratory, Alderley Park, Macclesfield, UK.
Brusick
D
D
Myhr
B C
BC
Jones
N J
NJ
Parry
J M
JM
Nesnow
S
S
Paton
D
D
Tinwell
H
H
Rosenkranz
H S
HS
Curti
S
S
D000814:Aniline Compounds / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity*; D007763:Lac Operon; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D010761:Phosphorus Radioisotopes; D011083:Polycyclic Compounds / Q000633:toxicity*; D012867:Skin / Q000187:drug effects; D012878:Skin Neoplasms / Q000139:chemically induced; D013876:Thiophenes / Q000633:toxicity*
D000814:Aniline Compounds; D002273:Carcinogens; D009153:Mutagens; D010761:Phosphorus Radioisotopes; D011083:Polycyclic Compounds; D013876:Thiophenes; C082386:6,11-dimethylbenzo(b)naphtho(2,3-d)thiophene; C050795:N,N-dimethyl-4-anisidine