Metabolic activation to a mutagen of 3-hydroxy-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, a secondary metabolite of benzo[a]pyrene.
3-Hydroxy-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (3-OH-BP-7,8-diol) was isolated from arylsulfatase/beta-glucuronidase-treated bile of rats to which 3-hydroxybenzo[a]pyrene (3-OH-BP) has been administered. This triol was investigated for mutagenicity in Salmonella typhimurium (reversion to histidine prototrophy of strains TA 97, TA 98, TA 100 and TA 1537) and in V79 Chinese hamster cells (acquisition of resistance to 6-thioguanine). When no exogenous metabolizing system was added the triol was inactive, while 3-OH-BP showed weak mutagenic effects with all four bacterial strains. In the presence of NADPH-fortified postmitochondrial supernatant fraction (S9 mix) of liver homogenate from Aroclor 1254-treated rats, the mutagenicity of 3-OH-BP was potentiated, and the triol was activated to a mutagen(s). In the presence of S9 mix, the triol was 5-18 times more mutagenic than 3-OH-BP in strains TA 97, TA 100 and TA 1537, but both compounds showed similar mutagenic potencies with strain TA 98. These strain differences strongly suggest that the mutagenicity of 3-OH-BP in the S9 mix-mediated test was not exclusively due to metabolites of 3-OH-BP-7,8-diol. Trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol), like the triol, showed mutagenic effects only in the presence of S9 mix. Strain TA 1537 was reverted by the triol but not by the diol. In the other bacterial strains the diol was more mutagenic than the triol, the difference in potency being largest in strain TA 100 (2.5- to 10-fold, depending on the experimental conditions). In V79 cells, the diol was a potent mutagen, while the triol showed only very weak mutagenic effects. However the triol was more cytotoxic than the diol. High cytotoxicity of the triol was observed even in the absence of S9 mix. The results of the present study demonstrate that metabolites of 3-OH-BP-7,8-diol are biologically-active derivatives of benzo[a]pyrene. Comparison of the mutagenic effectiveness in different bacterial strains also reveals that metabolites of 3-OH-BP-7,8-diol and of BP-7,8-diol substantially differ in the kind of genetic alterations they evoke.
Glatt
H
H
Institute of Toxicology, University of Mainz, FRG.
Seidel
A
A
Ribeiro
O
O
Kirkby
C
C
Hirom
P
P
Oesch
F
F
D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism*; D001580:Benzopyrenes / Q000633:toxicity; D001711:Biotransformation; D002478:Cells, Cultured; D004101:Dihydroxydihydrobenzopyrenes / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship
D001580:Benzopyrenes; D004101:Dihydroxydihydrobenzopyrenes; D009153:Mutagens; C017228:benzo(a)pyrene 7,8-dihydrodiol; D001564:Benzo(a)pyrene; C021338:3-hydroxybenzo(a)pyrene; C046695:3-hydroxy-7,8-dihydro-7,8-dihydroxybenzo(a)pyrene