In vitro embryotoxicity of N-methyl-N-(7-propoxynaphthalene-2-ethyl)hydroxylamine (QAB): evidence for N-dehydroxylated metabolite as a proximate dysmorphogen.
The rat conceptus biotransforms N-methyl-N-(7-propoxynaphthalene-2-ethyl)hydroxylamine (QAB) in vitro to 7-propoxynaphthalen-2-ylacetic acid (QAA) and six more (M1 to M6) metabolites. Thus far, M4 has been identified as N-demethyl-QAB and M6 as N-desoxy-QAB. We investigated which of these two metabolites might be involved in QAB-embryotoxicity in vitro. Conceptuses were cultured from day 9.5 to 11.5 post-coitum, and were exposed to N-demethyl-QAB or N-desoxy-QAB either in the culture medium or by microinjection directly into the amniotic cavity. When added to the culture medium, N-demethyl-QAB (No Observed Adverse Effect Level, NOAEL, for growth 122 microM and for differentiation 41 microM) was less active than QAB itself (NOAEL for growth and differentiation 12 microM). N-desoxy-QAB caused severe growth retardation and an impairment of differentiation at a concentration of 11 microM (NOAEL 3.6 microM). As regards causing anomalies, the NOAEL of N-demethyl-QAB (41 microM) was 10-fold higher than that of QAB (NOAEL 3.9 microM) and that of N-desoxy-QAB (NOAEL 3.6 microM). At an intraamniotic concentration of 0.7 mM, N-demethyl-QAB caused no effects on growth and differentiation and no increase of anomalies was observed, whereas QAB and N-desoxy-QAB each elicited an increase in dysmorphogenic embryos at equimolar concentrations without affecting growth and differentiation. It is, therefore, concluded that N-desoxy-QAB, but not N-demethyl-QAB, could be a proximate dysmorphogen responsible for the embryotoxicity/teratogenicity of QAB in vitro.
Terlouw
G D
GD
Drug Safety Assessment, Toxicology Department, Sandoz Pharma Ltd., Basle, Switzerland.
Namkung
M J
MJ
Juchau
M R
MR
Bechter
R
R
D000014:Abnormalities, Drug-Induced; D000818:Animals; D001711:Biotransformation; D004622:Embryo, Mammalian / Q000187:drug effects; D005260:Female; D006900:Hydroxylation; D009281:Naphthalenes / Q000378:metabolism / Q000633:toxicity*; D009924:Organ Culture Techniques; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013723:Teratogens / Q000378:metabolism / Q000633:toxicity*
D009281:Naphthalenes; D013723:Teratogens; C050439:N-hydroxy-N-methyl-7-propoxy-2-naphthaleneethanamine