Evaluation of the developmental toxicity of benzo[a]pyrene and 2-acetylaminofluorene using Xenopus: modes of biotransformation. Stover Group.
The developmental toxicities of benzo[a]pyrene (BAP) and 2-acetylaminofluorene (AAF) were evaluated using FETAX (Frog Embryo Teratogenesis Assay-Xenopus). Young X. laevis embryos were exposed to these two compounds in each of two separate concentration-response experiments with and without an exogenous metabolic activation system (MAS) and/or inhibited MAS. The MAS was treated with cimetidine (CIM), ellipticine (ELL), or alpha-napthoflavone (alpha-N) to selectively modulate cytochrome P-450 activity. Bioactivation of both of these compounds was indicated by increased developmental toxicity observed in MAS tests. Results obtained in treated MAS tests indicated that BAP was predominantly activated by Cytochrome P-450 isozyme CYP1A1. AAF bioactivation was shown to be only partly mediated by CYP1A1/2. Detoxification pathways for these two compounds were investigated by treatment of the MAS with cyclohexene oxide (CHO) and diethyl maleate (DM) to inhibit the epoxide hydroxylase and glutathione conjugation pathways, respectively. Results indicated that epoxide hydroxylase was primarily responsible for the detoxification of BAP, with glutathione conjugation playing a secondary role. Detoxification of AAF by these two pathways was not indicated.
Propst
T L
TL
Department of Zoology, Oklahoma State University, Stillwater, USA.
Fort
D J
DJ
Stover
E L
EL
Schrock
B
B
Bantle
J A
JA
D015073:2-Acetylaminofluorene / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000633:toxicity*; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation; D002273:Carcinogens / Q000633:toxicity*; D002927:Cimetidine / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology; D053138:Cyclohexenes; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004611:Ellipticines / Q000494:pharmacology; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D008297:Male; D008298:Maleates / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D014982:Xenopus laevis / Q000196:embryology
D000970:Antineoplastic Agents; D001571:Benzoflavones; D002273:Carcinogens; D003510:Cyclohexanes; D053138:Cyclohexenes; D004611:Ellipticines; D006635:Histamine H2 Antagonists; D008298:Maleates; C034192:ellipticine; C007193:cyclohexene oxide; D001564:Benzo(a)pyrene; C011512:alpha-naphthoflavone; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D015073:2-Acetylaminofluorene; D019363:Cytochrome P-450 CYP1A1; D004851:Epoxide Hydrolases; C014476:diethyl maleate; D005978:Glutathione