Diethylhexyl phthalate (DEHP) is one of the most widely utilized phthalate plasticizers. Previous studies have demonstrated that gestational or postnatal DEHP exposure induced adverse effects on rat brain development and function. In this study, we investigated the effects of gestational DEHP exposure on gene expression profiling in neonatal rat brain and cognitive function change at adulthood. Adult Sprague Dawley dams were orally treated with 10 or 750 mg/kg DEHP from gestational day 12 to 21. Some male pups were euthanized at postnatal day 1 for gene expression profiling, and the rest males were retained for water maze testing on postnatal day (PND) 56. DEHP showed dose-dependent impairment of learning and spatial memory from PND 56 to 63. Genome-wide microarray analysis showed that 10 and 750 mg/kg DEHP altered the gene expression in the neonatal rat brain. Ccnd1 and Cdc2, two critical genes for neuron proliferation, were significantly down-regulated by DEHP. Interestingly, 750 mg/kg DEHP significantly increased Pmch level. Our study demonstrated the changed gene expression patterns after in utero DEHP exposure might partially contribute to the deficit of cognitive function at adulthood.

Aim: Human cytochrome P450 3A4 is the most abundant isoform of P450 enzyme in the liver. It plays an important role in the metabolism of wide variety of xenobiotic and endogenous substrates. So far, there are few reports about the functional characterization of CYP3A4 variants in terms of specific substrates. The aim of this study was to systematically investigate the genetic polymorphisms of 23 CYP3A4 alleles and evaluate their catalytic activities on the metabolism of lidocaine in vitro. Methods and results: The wild-type and 22 CYP3A4 variants were expressed in Spodoptera frugiperda 21 insect cells. Then the insect microsomes were incubated with the CYP3A4-specific substrate lidocaine. Reactions were performed with 50–3,000 µM for 60 min at 37°C. Lidocaine and its metabolite monoethylglycinexylidide were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry system. Of the 23 CYP3A4 allelic variants tested, 2 variants (CYP3A4*17 and CYP3A4*30) had no detectable enzyme activity; and 5 variants (CYP3A4*2, CYP3A4*5, CYP3A4*9, CYP3A4*16 and CYP3A4*24) showed significantly decreased intrinsic clearance values compared with wild-type CYP3A4*1. Conclusion: As the first study of all these CYP3A4 alleles for lidocaine metabolism, our results in vitro assessment may provide novel insights into the allele-specific and substrate-specific activity of CYP3A4 and may also offer a reference to the personalized treatment of lidocaine in a clinical setting.