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Biomedical subjects

G H Lambert

Publications and source records attributed to G H Lambert.

31 records · Page 2Linked to original sources
PubMed1987

Effects of pregnancy on the cytochrome P-450 system in mice.

The effects of pregnancy on the hepatic cytochrome P-450-dependent mixed-function monooxygenase system (P-450) from day 6 to day 18 of gestation were examined in the C57BL/6J mouse. Pregnancy induced an initial increase and then a decrease in total P-450 content, a decrease in microsomal aminopyrine-N-demethylase activity, and had no effect on microsomal ethylmorphine-N-demethylase activity. Pregnancy also induced in the C57BL/6J and the DBA/2J mice a new major isozyme of P-450 (P-450gest) as determined by high performance liquid chromatography and gel electrophoresis.

Aminopyrine N-Demethylase↗
PubMed1987

Dynamic trend monitoring of cerebral blood flow velocity in newborn infants.

A method for obtaining reproducible Doppler cerebral blood flow velocity (CBFV) measurements over several hours, utilizing a probe fixation technique and an on-line system for making beat-to-beat area under the curve (AUC) measurements, is described. Thirty heartbeat samples were collected at three time intervals over 3 hours in a group of 22 healthy preterm infants. The stability of the AUC measurements despite changes in behavioral state was demonstrated by randomized block ANOVA. The sampling error was +/- 6.92%, with 95% confidence intervals of +/- 13.1%. By facilitating reproducible serial measurements of CBFV, this trend monitoring technique encourages a dynamic view of cerebrovascular control, and may be used to probe central nervous system autoregulatory pathophysiology and to evaluate the effects of therapeutic interventions.

Blood Flow Velocity↗
PubMed1986

The effect of age, gender, and sexual maturation on the caffeine breath test.

This study demonstrated the feasibility of utilizing the (3-13C-methyl) caffeine breath test (CBT) in children and adolescents, and examined the effect of gender, age, and puberty on the CBT. The CBT, expressed as the 2-hour accumulative exhalation of labeled CO2 (2-hour CO2), was compared to the CBT results in the adult. The 2-hour CO2 values were higher in the children than the adult, and the decrease in the CO2 values occurred in males during late puberty and in females during early puberty.

Adolescent↗
PubMed1983

The CO2 breath tests as monitors of the cytochrome P450 dependent mixed function monooxygenase system.

The CBT and ABT are simple to conduct and are sensitive, reproducible monitors of hepatic enzyme function. They monitor functional hepatic mass at the time the tests are conducted and are specific monitors of P1-450 and P-450 function. In the animal model, the breath test can be conducted repeatedly, thus making it easier to monitor hepatic enzyme function throughout the animal's development, during pregnancy, or before and after administration of xenobiotics. Because of this, the breath test requires fewer animals and less technician time than standard in vitro assays and reduces costs. The breath tests' simplicity, noninvasive nature, and safety (especially the CBT) combined with a high degree of sensitivity and reproducibility make them ideal for nontherapeutic clinical research in large numbers of humans, particularly in the pediatric patient, where risks must be almost negligible. The breath tests are especially well suited for the examination of the many-faceted relationships between xenobiotics and MFOS, and in particular those correlations which are unique concerns of developmental pharmacology and toxicology.

Animals↗
PubMed1982

The caffeine CO2 breath test: dose response and route of N-demethylation in smokers and nonsmokers.

The optimal conditions for performing the caffeine CO2 breath test (CBT) were investigated in smokers and nonsmokers. Caffeine labeled with 13C or 14C in all three (1, 3, and 7) methyl groups or specifically in the 1-, 3-, or 7-methyl groups were orally administered to healthy adults and the expiration of labeled CO2 was measured for 8 or 24 hr. The absolute rate of labeled CO2 excretion from trilabeled caffeine was proportional to the dose up to 3 mg/kg in all subjects. In smokers, the rate of labeled CO2 excretion averaged twice that in nonsmokers at all doses. A correlation was observed between the 2-hr cumulative CO2 excretion from trilabeled caffeine and the apparent oral metabolic clearance rate (MCR) of caffeine (R = 0.90). Monolabeled CBTs in smokers and nonsmokers demonstrated that 80% +/- 4% of labeled CO2 expired in the breath during the first 2 hr of a trilabeled CBT was derived from the 3 position; at 6 to 8 hr equal amounts were derived from the 3 and 7 positions. Little N-demethylation was observed from the 1 position at any time during the 8-hr test. The results indicate that the 2-hr cumulative excretion of labeled CO2 could be used to accurately predict the metabolic clearance rate of caffeine is the best CBT parameter for detecting the effect of smoking on caffeine N-demethylation. The data suggest that the primary routes of caffeine metabolism are 3-N-demethylation and ring hydroxylation and confirm that caffeine metabolites are N-demethylated primarily in the 3 and 7 positions.

Adult↗
PubMed1977

Genetically mediated induction of drug-metabolizing enzymes associated with congenital defects in the mouse.

Various polycyclic aromatic compounds induce certain monooxygenase activities, including aryl hydrocarbon (benzo[a]pyrene) hydroxylase (EC 1.14.14.2), and cytochrome P1-450 in the liver and many nonhepatic tissues of the mouse. This induction process is controlled by the Ah locus. Genetic differences that have been shown in the past to be associated with the Ah locus include an increased susceptibility to chemical carcinogenesis, mutagenicity in vitro, and drug toxicity--manifested as hepatic necrosis, aplastic anemia, or shortened survival time. Pregnant mice received a single injection of 3-methylcholanthrene or 7,12-dimethylbenz[a] anthracene between day 5 and day 13 of gestation, and the uterine contents were examined on day 18. Striking increases were observed in the incidence of MC-1 and DMBA-induced resorptions and congenital malformations in the aromatic hydrocarbon "responsive" C57BL/6N inbred strain, and of DMBA-induced resorptions in the "responsive" C3H/HeN and BALB/cAnN strains--when compared with the similarly treated genetically "nonresponsive" AKR/N strain. These data suggest but do not prove that an association exists between the Ah locus and developmental toxicity, i.e., teratogenesis. Although numerous teratogenic differences among inbred mouse strains have previously reported, this study is unique in that the genetic differences in teratogenicity observed were predicted in advance on the basis of known differences among these strains in polycyclic hydrocarbon metabolism regulated by the Ah locus.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1976

Genetic aspects of toxicity during development.

The Ah locus in the mouse controls the induction of cytochrome P1-450 and at least eleven associated monooxygenase activities. These enzyme systems metabolically potentiate and detoxify drugs, environmental pollutants, and other foreign chemicals, as well as numerous endogenous substrates. For certain substrates, it is known that cytochrome P1-450 produces different reactive intermediates and products that other forms of P-450. Alleles at the Ah locus can be identified in utero. Development toxicity (in the form of stillborns, resorptions, and malformations of the fetus) by 3-methylcholanthrene and 7,12-dimethylbenz[a]anthracene given to the pregnant mother is associated with genetically mediated aromatic hydrocarbon responsiveness in C5BL/6N mice, compared with that in nonresponsive AKR/N mice. Acetaminiphen-produced hepatic necrosis is associated with glutathione depletion in the liver, covalent binding of metabolite(s) of the drug to cellular macromolecules, and P1-450 induction controlled by the Ah locus. For reasons not known, the fetus and mice 10 days of age or less are relatively resistant to glutathione depletion and therefore hepatic necrosis by acetaminophen.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Comparison of the phenacetin and aminopyrine breath tests: effect of liver disease, inducers and cobaltous chloride.

The phenacetin breath test (PBT) has been proposed as an alternative to the aminopyrine breath test (ABT) for the assessment of hepatic function. To investigate the clinical utility of the PBT, we compared the PBT with the ABT in 9 healthy subjects and 18 patients with biopsy-proven liver disease. We also investigated the effects of cytochrome P-450 inducers in humans and rats, and the effect of cobaltous chloride (CoCl2) in rats on the PBT to elucidate the relationship between the rate of phenacetin deethylation and exhaled labeled CO2 derived from phenacetin. In humans with abnormal ABTs, the PBT correlated with the ABT (r = 0.77), but in healthy humans there was no correlation between the two breath tests. Rifampin pretreatment in healthy humans induced the ABT by 27%, but did not induce the PBT. In rats the PBT was not induced by 3-methylcholanthrene pretreatment at phenacetin doses of 1 mg per kg, but was induced by both 3-methylcholanthrene (178%) and phenobarbital (142%) at 10 mg per kg phenacetin. Pretreatment of rats with CoCl2, which reduces cytochrome P-450 content, decreased the PBT by 40% and the ABT by 84%. The insensitivity of the PBT to induction except at high doses of phenacetin suggests that phenacetin deethylation is not the rate-limiting process modulating exhaled labeled CO2 in healthy subjects, and that the PBT does not generally reflect normal or induced phenacetin dealkylation rates. The PBT, however, did reflect hepatic damage and may even be better than the ABT for grading the severity of hepatic damage.

Adult↗