Toxicology Letters 167 (2006) 245–255 Foetal and adult human CYP3A isoforms in the bioactivation of organophosphorothionate insecticides Franca M. Buratti, Claudia Leoni, Emanuela Testai ∗ Environment and Primary Prevention Department, Istituto Superiore di Sanit` a, Viale Regina Elena 299, I-00161 Rome, Italy Received 27 July 2006; received in revised form 9 October 2006; accepted 13 October 2006 Available online 24 October 2006 Abstract In humans organophosphorothionate pesticides (OPT) prenatal exposure has been demonstrated. Since OPT-induced neurode- velopmental 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 M). 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. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Organophosphorothionate pesticides; CYP3A7; CYP3A4; CYP3A5; Foetal metabolism 1. Introduction Organophosphorothionates (OPTs) are among the most widely used insecticides around the world, both Abbreviations: AChE, acetylcholinesterase; AcThCh, acetylth- iocholine; CLi, intrinsic clearance; CPF, chlorpyrifos; CPFO, chlorpyrifos-oxon; DTNB, dithiobisnitrobenzoic acid; FEN, fen- thion; FOX, fenthion oxon; MAL, malathion; MOX, malaoxon; OPT, organophosphorothionate; PAR, parathion; PON1, paraoxonase 1; POX, paraoxon; PYR, 3,5,6-trichloropyrin-2-ol ∗ Corresponding author at: Environment and Primary Prevention Department, Istituto Superiore di Sanit` a, Mechanisms of Toxicity Unit, Viale Regina Elena 299, I-00161 Rome, Italy. Tel.: +39 06 4990 2920; fax: +39 06 4938 7139. E-mail address: emanuela.testai@iss.it (E. Testai). in agriculture and in domestic buildings. Due to their efficacy, relatively low cost and low potential for bioac- cumulation and persistence in the environment, it is not expected that their use will decrease in the next future. Therefore, beside professional users, a large part of the general population has been and will continue to be exposed, and concerns for their known and potentially new adverse effects will remain alive. OPT-induced acute effects, mediated by the acetyl- cholinesterase (AChE) inhibition in synapses and neu- romuscular junctions (Forsyth and Chambers, 1989), are responsible for most of the thousands deaths, annu- ally reported around the world, associated with pesticide accidental or intentional intoxications (Eddleston, 2000; Eddleston and Phillips, 2004; Yasmashita et al., 1997). 0378-4274/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.toxlet.2006.10.006