Aims To investigate the influence of the CYP1A2 * 1F mutation on CYP1A2 activity in smoking and nonsmoking pregnant women. Methods Pregnant women ( n = 904) who served as control subjects in a case-control study of early fetal loss were investigated. They were phenotyped for CYP1A2 using dietary caffeine and the urinary ratio AFMU + 1X + 1 U/1,7 U. An assay for CYP1A2 * 1F using 5 ¢ -nuclease assay (Taqman) was developed to genotype the population. Results The frequencies of * 1 A and * 1F alleles among Swedish women were 0.29 and 0.71, respectively. There was no statistically significant difference in CYP1A2 activity between the genotypes, although a trend towards enhanced activity was observed in * 1F / * 1F (log MR c 0.77) and * 1F/ * 1 A (log MR c 0.82) genotypes compared with the * 1 A/ * 1 A genotype (log MR c 0.71) ( ANOVA P = 0.07). The mean difference between the * 1 A homozygotes and the heterozygotes was 0.11 [95% confidence interval of the difference: ( -0.21, -0.01)] and that between the * 1 A and * 1F homozygotes was 0.05 [95% confidence interval of the difference: ( -0.13, 0.03)]. No significant effect ( P = 0.22) of the * 1F on CYP1A2 activity was observed in smokers, tested using an interaction term (smoking * genotype) in the ANOVA model (* 1F / * 1F log MR c 0.79, * 1F/ * 1 A log MR c 0.86, and * 1 A/ * 1 A log MR c 0.73). In smokers, there was no difference in ratio between homozygotes for the * 1 A and * 1F alleles [mean difference -0.06; 95% confidence interval of the difference: -0.22, 0.11] or between * 1 A/ * 1 A and * 1 A/ * 1F genotypes [mean difference -0.13; 95% confidence interval of the difference: -0.29, 0.04]. Conclusions The effect of the CYP1A2 * 1F mutation on CYP1A2 activity in smoking pregnant women could not be confirmed.
The opioid receptor binding in the human thalamic area was studied with U-69593 and naloxone as ligands for the kappa and mu receptors, respectively. The binding was inhibited by various tricyclic antidepressants including amitriptyline, nortriptyline, clomipramine and fluoxetine. The antidepressants tested had a slight selectivity for the kappa receptor type. The IC50-values for all tricyclic antidepressants tested were in the 10(-6) M concentration range. Morphine and tricyclic antidepressants are substrates of a liver microsomal uridine diphosphate glucuronyl transferase (UDPGT). The interaction of the tricyclic antidepressants with morphine glucuronidation was investigated in human liver microsomal preparations. All drugs inhibited the morphine UDPGT. In Dixon plots inhibition of the formation of morphine-3-glucuronide and morphine-6-glucuronide was non-competitive for nortriptyline, and competitive or mixed for amitriptyline and clomipramine. Lubrol PX activated the morphine-UDPGT four to five times. The degree of activation of the enzyme(s) was unaltered in presence of the inhibiting drugs. The inhibition was also observed at a tricyclic antidepressant/morphine concentration ratio close to that achieved in plasma from patients treated with these drugs.
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