CYP3A4 induction by xenobiotics: biochemistry, experimental methods and impact on drug discovery and development.

Cytochrome P450 3A4 (CYP3A4), an enzyme that is highly expressed in the human liver and small intestine, plays a major role in the metabolism of a large variety of xenobiotics, including an estimated 50% of therapeutic drugs, as well as many endogenous compounds. The expression of CYP3A4 can be induced by xenobiotics. Such induction leads to accelerated metabolism of the xenobiotics themselves (autoinduction) or of concomitantly administered CYP3A4 substrates/drugs, thereby significantly altering their pharmacokinetic and pharmacodynamic profiles.

Investigation of the role of the 2',3'-epoxidation pathway in the bioactivation and genotoxicity of dietary allylbenzene analogs.

The genotoxic potential of naturally occurring allylbenzene analogs, including safrole, eugenol, estragole, and others, has been examined in many studies over the past 30 years. It has been established that these compounds are subject to biotransformation in the liver, which can lead to the formation of reactive electrophilic intermediates. The major route of bioactivation is via hydroxylation of the 1' carbon atom of the allylic side chain.

Goldschlager allergy in a gold allergic patient.

We describe the case of gold allergy after ingestion of GOLDSCHLAGER, a gold-containing liquor, in a patient with a previous allergy to gold jewelry. The patient was not aware that genuine gold particles were contained in the schnapps liquor and that ingestion could result in a reaction similar to that experienced by individuals sensitive to gold jewelry. Clinicians should be familiar with the presence of gold particles in GOLDSCHLAGER liquor and the potential for allergic reactions to occur in those so predisposed.

Isolation of liver nuclei that retain functional trans-membrane transport.

We have developed a method for the rapid isolation of hepatocyte nuclei, which employs gentle homogenization and centrifugation conditions, and involves minimal processing time. The purified nuclei were morphologically unaltered when observed by light and electron microscopy. No significant contamination from cytoplasm or mitochondria was detected when assessed by marker enzymes.

Co-purification of microsomal epoxide hydrolase with the warfarin-sensitive vitamin K1 oxide reductase of the vitamin K cycle.

Vitamin K1 oxide reductase activity has been partially purified from rat liver microsomes. A three-step procedure produced a preparation in which warfarin-sensitive vitamin K1 oxide reductase activity was 118-fold enriched over the activity in intact rat liver microsomes. A major component of the multi-protein mixture was identified as a 50 kDa protein that strongly cross-reacts with antiserum prepared against homogeneous rat liver microsomal epoxide hydrolase.