Studies on induction of lamotrigine metabolism in transgenic UGT1 mice.

A transgenic 'knock-in' mouse model expressing a human UGT1 locus (Tg-UGT1) was recently developed and validated. Although these animals express mouse UGT1A proteins, UGT1A4 is a pseudo-gene in mice. Therefore, Tg-UGT1 mice serve as a 'humanized' UGT1A4 animal model. Lamotrigine (LTG) is primarily metabolized to its N-glucuronide (LTGG) by hUGT1A4. This investigation aimed at examining the impact of pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor (PPAR) activators on LTG glucuronidation in vivo and in vitro. Tg-UGT1 mice were administered the inducers phenobarbital (CAR), pregnenolone-16alpha-carbonitrile (PXR), WY-14643 (PPAR-alpha), ciglitazone (PPAR-gamma), or L-165041 (PPAR-beta), once daily for 3 or 4 days. Thereafter, LTG was administered orally and blood samples were collected over 24 h. LTG was measured in blood and formation of LTGG was measured in pooled microsomes made from the livers of treated animals. A three-fold increase in in vivo LTG clearance was seen after phenobarbital administration. In microsomes prepared from phenobarbital-treated Tg-UGT1 animals, 13-fold higher CL(int) (Vmax/K(m)) value was observed as compared with the untreated transgenic mice. A trend toward induction of catalytic activity in vitro and in vivo was also observed following pregnenolone-16alpha-carbonitrile and WY-14643 treatment. This study demonstrates the successful application of Tg-UGT1 mice as a novel tool to study the impact of induction and regulation on metabolism of UGT1A4 substrates.

Thermochemical remanent magnetization and thermal remanent magnetization: comparison in a basalt.

Recent studies have shown that the remanent magnetization carried by an extrusive igneous rock may not be entirely thermal remanent magnetization (TRM). Some may be thermochemical remanent magnetization (TCRM) acquired by the rock at temperatures at least as low as 300 degrees C during oxidation of the contained titanomagnetite grains. Results from a study of a set of basaltic samples from one locality indicate that the intensity of TCRM acquired by a sample in a known magnetic field is equal to that of TRM subsequently produced in the same sample in the same field. On the assumption that the samples we studied are not magnetically unique, we tentatively conclude that paleointensity studies are valid in spite of the presence of TCRM, as long as the rock acquired the magnetization during the initial cooling.

Magnetic properties of lunar samples.

A breccia sample (10023) from the moon was found to have a strong and fairly stable remanent magnetization. If this sample was not magnetized by local fields in the spacecraft or in the lunar receiving laboratory, it must have been magnetized on the moon. This could have happened in a variety of ways, such as cooling through the Curie temperature, by comitinuous thermal cycling, or by impact, but all of these require the presence ofr a magnetic field. Such a field could have been of internal origin in the moon, or it could have been a residual effect from the earth's magnetic field at a time when the moon and the earth were much closer together. Thermomagnetic studies identify the presence of iron with about 1 percent nickel (igneous). iron with abiout 5 to 10 percent nickel (meteoritic), iron with about 33 percent or more nickel (meteoritic), and ilmenite.