Scaling in vitro activity of CYP3A7 suggests human fetal livers do not clear retinoic acid entering from maternal circulation.

All-trans-retinoic acid (atRA), the active metabolite of vitamin A, is a critical signaling molecule during embryonic and fetal development and is necessary for maternal health. Fetal exposure to endogenous atRA is tightly regulated during gestation in a tissue specific manner and maternal exposure to exogenous retinoids during pregnancy is teratogenic. The clearance of atRA is primarily mediated by the cytochrome P450 (CYP) 26 enzymes, which play an essential role in controlling retinoid gradients during organogenesis.

Toxicokinetics and Physiologically Based Pharmacokinetic Modeling of the Shellfish Toxin Domoic Acid in Nonhuman Primates.

Domoic acid (DA), a neurotoxin, is produced by marine algae and has caused toxications worldwide in animals and humans. However, the toxicokinetics of DA have not been fully evaluated, and information is missing on the disposition of DA following oral exposures at doses that are considered safe for human consumption. In this study, toxicokinetics of DA were investigated in cynomolgus monkeys following single doses of 5 g/kg DA intravenously, 0.

Ultra-high performance liquid chromatography tandem mass-spectrometry for simple and simultaneous quantification of cannabinoids.

Cannabis is used widely in the United States, both recreationally and for medical purposes. Current methods for analysis of cannabinoids in human biological specimens rely on complex extraction process and lengthy analysis time. We established a rapid and simple assay for quantification of Δ-tetrahydrocannabinol (THC), cannabidiol (CBD), 11-hydroxy Δ-tetrahydrocannabinol (11-OH THC) and 11-nor-9-carboxy-Δ-tetrahydrocannbinol (THCCOOH) in human plasma by U-HPLC-MS/MS using as the internal standard.

Induction of CYP26A1 by metabolites of retinoic acid: evidence that CYP26A1 is an important enzyme in the elimination of active retinoids.

All-trans-retinoic acid (atRA), the active metabolite of vitamin A, induces gene transcription via binding to nuclear retinoic acid receptors (RARs). The primary hydroxylated metabolites formed from atRA by CYP26A1, and the subsequent metabolite 4-oxo-atRA, bind to RARs and potentially have biologic activity. Hence, CYP26A1, the main atRA hydroxylase, may function either to deplete bioactive retinoids or to form active metabolites.

Pharmacogenetic predictors of nausea and vomiting of pregnancy severity and response to antiemetic therapy: a pilot study.

Background: Nausea and vomiting of pregnancy (NVP) is a common condition. The objective of this study was to evaluate the association between response to antiemetics in the treatment of NVP and genetic polymorphisms in the serotonin receptor subunit genes HTR3A and HTR3B.

Methods: Pregnant women ≥18 years of age with NVP starting antiemetic therapy with promethazine, prochlorperazine, metoclopramide, or ondansetron at ≤ 16 weeks gestational age were eligible.

The relative contributions of CYP3A4 and CYP3A5 to the metabolism of vinorelbine.

Vinorelbine is a semisynthetic vinca alkaloid used in the treatment of advanced breast and non-small cell lung cancers. Vincristine, a related vinca alkaloid, is 9-fold more efficiently metabolized by CYP3A5 than by CYP3A4 in vitro. This study quantified the relative contribution of CYP3A4 and CYP3A5 to the metabolism of vinorelbine in vitro using cDNA-expressed human cytochrome P450s (P450s) and human liver microsomes (HLMs).

Hepatic Cyp2d and Cyp26a1 mRNAs and activities are increased during mouse pregnancy.

There is considerable evidence that drug disposition is altered during human pregnancy and based on probe drug studies, CYP2D6 activity increases during human pregnancy. The aim of this study was to determine whether the changes of CYP2D6 activity observed during human pregnancy could be replicated in the mouse, and explore possible mechanisms of increased CYP2D6 activity during pregnancy. Cyp2d11, Cyp2d22, Cyp2d26 and Cyp2d40 mRNA was increased (P < 0.

Stereoselective formation and metabolism of 4-hydroxy-retinoic Acid enantiomers by cytochrome p450 enzymes.

All-trans-retinoic acid (atRA), the major active metabolite of vitamin A, plays a role in many biological processes, including maintenance of epithelia, immunity, and fertility and regulation of apoptosis and cell differentiation. atRA is metabolized mainly by CYP26A1, but other P450 enzymes such as CYP2C8 and CYP3As also contribute to atRA 4-hydroxylation. Although the primary metabolite of atRA, 4-OH-RA, possesses a chiral center, the stereochemical course of atRA 4-hydroxylation has not been studied previously.

Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases.

All-trans-retinoic acid (atRA) is an important signaling molecule in all chordates. The cytochrome P450 enzymes CYP26 are believed to partially regulate cellular concentrations of atRA via oxidative metabolism and hence affect retinoid homeostasis and signaling. CYP26A1 and CYP26B1 are atRA hydroxylases that catalyze formation of similar metabolites in cell systems.

Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia.

Background: This study evaluates the relationship between cytochrome P450 (CYP) 3A5 genotype and vincristine-induced peripheral neuropathy (VIPN) in children with precursor B cell acute lymphoblastic leukemia (preB ALL). We have shown in vitro that vincristine is metabolized significantly more efficiently by CYP3A5 than by CYP3A4. We also found that vincristine neurotoxicity is less common in African-Americans (70% express CYP3A5) than in Caucasians.