Foetal and adult human CYP3A isoforms in the bioactivation of organophosphorothionate insecticides.
In humans organophosphorothionate pesticides (OPT) prenatal exposure has been demonstrated. Since OPT-induced neurodevelopmental effects may be due to in situ bioactivation by foetal enzymes, the catalytic activity of the foetal CYP3A7 toward chlorpyrifos (CPF), parathion (PAR), malathion (MAL) and fenthion (FEN) has been assessed by using recombinant enzymes. A comparison with the adult isoforms CYP3A4 and CYP3A5 has been also carried out. CYP3A7 was able to produce significant levels of oxon or sulfoxide from the four OPTs in the range of tested concentrations (0.05-200 microM). When the efficiencies of CYP3A isoforms were compared, the ranking, expressed as CLi values, were: CPF=3A4>3A5>3A7; PAR=3A4>>3A7>>3A5; MAL=3A4>3A7>3A5; FEN (sulfoxide formation)=3A4>3A5>>3A7. The CYP3A5 efficiency appeared to be more dependent on the single insecticide than its related isozyme CYP3A4. Our results indicate that the levels of toxic metabolite formed in situ by CYP3A7 from CPF, MAL and PAR but not from FEN have the chance to inhibit acetylcholinesterase, following prenatal exposure to OPTs. However, due to the smaller weight of foetal liver, the contribution to total OPT biotransformation is relatively low. On the other hand, our results clearly indicate that at low CPF concentrations, the formation of the non-toxic metabolites is highly favoured in the foetus.
Buratti
Franca M
FM
Environment and Primary Prevention Department, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy.
Leoni
Claudia
C
Testai
Emanuela
E
D000818:Animals; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D005333:Fetus / Q000201:enzymology*; D007306:Insecticides / Q000493:pharmacokinetics*; D007527:Isoenzymes / Q000502:physiology*; D009946:Organothiophosphorus Compounds / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007306:Insecticides; D007527:Isoenzymes; D009946:Organothiophosphorus Compounds; D003577:Cytochrome P-450 Enzyme System; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A