Heterozygous apolipoprotein (a) status and protein expression as a risk factor for premature coronary heart disease.

Exactly how apolipoprotein a [APO(a)] isoform size affects the degree of cardiovascular risk associated with high lipoprotein a [LP(a)] levels is not fully understood. Using a sodium dodecyl sulfate-agarose APO(a) & LP(a) phenotyping method, we assessed the role of APO(a) size heterogeneity according to the number of kringle 4 repeats and the differential APO(a) protein expression in 91 male Spanish patients with premature coronary heart disease (CHD) compared with 99 healthy Spanish men. CHD patients had significantly increased median plasma LP(a) levels (0.

Metabolism of R,S enantiomers of 3-phenylamino-1,2-propanediol, a compound associated with the toxic oil syndrome, in C57BL/6- and A/J-strain mice.

PAP, a very polar substance, is highly metabolized in mice and excreted principally in urine in the form of the 2-hydroxy-3-phenylaminopropanoic acid of each enantiomer. Thus, the major route of PAP elimination in these strains is alkyl chain oxidation. In particular, S-PAP is eliminated principally in the form of that metabolite, whereas R-PAP enantiomer showed further oxidized species at the aromatic ring and alkyl chain, yielding potential decarboxylated compounds and iminoquinones.

SHV-1 beta-lactamase is mainly a chromosomally encoded species-specific enzyme in Klebsiella pneumoniae.

The nature of the SHV-1 beta-lactamase gene was analyzed in 97 epidemiologically unrelated Klebsiella pneumoniae strains isolated from clinical samples. beta-Lactamase bands that focused at a pI of 7.6 (SHV-1-type) in 74 strains, at a pI of 7.

Metabolism of (R)- and (S)-3-(phenylamino)propane-1,2-diol in C57BL/6- and A/J-strain mice. Identification of new metabolites with potential toxicological significance to the toxic oil syndrome.

The Toxic Oil Syndrome was a massive food-borne intoxication that occurred in Spain in 1981. Epidemiological studies point to 3-(phenylamino)propane-1,2-diol (PAP) derivatives as the putative toxic agents. We report further identification of metabolites cleared in urine of A/J and C57BL/6 mice in which (R)- and (S)-3-(phenylamino)propane-1,2-diol were administered intraperitoneally.

Pharmacogenetic profile of xenobiotic enzyme metabolism in survivors of the Spanish toxic oil syndrome.

In 1981, the Spanish toxic oil syndrome (TOS) affected more than 20,000 people, and over 300 deaths were registered. Assessment of genetic polymorphisms on xenobiotic metabolism would indicate the potential metabolic capacity of the victims at the time of the disaster. Thus, impaired metabolic pathways may have contributed to the clearance of the toxicant(s) leading to a low detoxification or accumulation of toxic metabolites contributing to the disease.

Cocaine metabolism in human fetal and adult liver microsomes is related to cytochrome P450 3A expression.

Cocaine N-demethylation to norcocaine was studied in human liver microsomes of different ages. Norcocaine was formed at a considerable rate in fetal (45.4+/-18.

Biotransformation and clearance of 3-(phenylamino)propane-1,2-diol, a compound present in samples related to toxic oil syndrome, in C57BL/6 and A/J mice.

In May 1981, a massive food-borne intoxication occurred in Spain. The so-called toxic oil syndrome (TOS) was associated with the consumption of aniline-denatured and refined rapeseed oil that was illegally sold as edible olive oil. Fatty acid anilides and fatty acid derivatives of 3-(phenylamino)propane-1,2-diol were detected in oils and implicated as potential toxic agents and markers of toxic oil batches.

Differential expression of double-band apolipoprotein(a) phenotypes in healthy Spanish subjects detected by SDS-agarose immunoblotting.

A sodium dodecyl sulphate-agarose apolipoprotein(a) [apo(a)] phenotyping method was set up to attain accurate scanning densitometry of proteins. Serum samples from 99 healthy Spanish men were analysed and twenty-five different apo(a) isoforms (12 to 37 kringle 4 repeats) were detected. Double-band phenotypes accounted for 39.

Blood levels of polychlorinated dibenzodioxins, polychlorinated dibenzofurans and polychlorinated biphenyls in the general population of a Spanish Mediterranean city.

Polychlorinated dibenzodioxins (PCDDs), Polychlorinated dibenzofurans (PCDFs) and Polychlorinated biphenyls (PCBs) are among the most toxic environmental pollutants. We determined blood levels of these compounds in a population sample of the city of Mataró, Spain. Blood samples were drawn from a randomly selected sample of 198 subjects, of both genders, aged 18 to 69 years.

CYP2D6 genotypes in Spanish women with breast cancer.

Wild type and three mutated alleles of the polymorphic CYP2D6 gene were studied in genomic DNA samples from 187 women with breast carcinoma and 151 healthy women by a mutation-specific polymerase chain reaction. The prevalence of the enzyme-inactivating CYP2D6(B) allele was higher among patients (18.2%) than in controls (11.

Genetic basis for differences in debrisoquin polymorphism between a Spanish and other white populations.

The debrisoquin hydroxylation polymorphism is an autosomic recessive trait of the cytochrome P450IID6, an enzyme involved in drug metabolism, that affects 5% to 10% of white subjects. The genetic basis of this polymorphism was studied in 258 unrelated Spanish white subjects. The results revealed that about 5% of the subjects were homozygous for mutant alleles and that about 1% of the subjects carried alleles that suggested CYP2D6 gene duplication.

Comparison of human fetal hepatic and adrenal cytochrome P450 activities with some major gestational steroids and ethylmorphine as substrates.

The immunoidentified human fetal liver and adrenal microsomal contents of cytochromes P450IIIA and P450XVIIA1 were compared to the metabolism of steroids and ethylmorphine. In fetal liver microsomes, 16 alpha-hydroxylation of dehydroepiandrosterone (DHA) was catalyzed at a high rate in almost all investigated specimens and accompanied by a high ethylmorphine N-demethylase activity. Progesterone 16 alpha- and 17 alpha-hydroxylation was found only in the livers with the highest DHA 16 alpha-hydroxylation activities, while 21-hydroxylation of progesterone was catalyzed only occasionally in these samples.

Characterization of the cytochrome P-450 gene family responsible for the N-dealkylation of the ergot alkaloid CQA 206-291 in humans.

The ergot alkaloid CQA 206-291 (CQA) was converted by human liver microsomes (n = 16) almost exclusively to the N-deethylated metabolite (I), as identified by the on-line coupling of liquid chromatography and mass spectroscopy. Metabolite I formation exhibited monophasic and linear enzyme kinetics (2.9-300 microM), and a 5.

Differential foetal development of the O- and N-demethylation of codeine and dextromethorphan in man.

1. Codeine and dextromethorphan were N-demethylated in human foetal liver microsomes at high rates which were close to the activities in adult livers. In contrast, foetal liver microsomes did not catalyze the O-demethylation of these drugs at mid-gestation.

Polymorphic formation of morphine from codeine in poor and extensive metabolizers of dextromethorphan: relationship to the presence of immunoidentified cytochrome P-450IID1.

We studied the oxidation capacity in liver biopsies of a series of extensive metabolizers (n = 10) and poor metabolizers (n = 2) as identified by in vivo phenotyping with dextromethorphan. Codeine and dextromethorphan were used as probe drugs in vitro. The data were compared with the contents of cytochrome P-450IID1 as quantitated by Western immunoblotting by use of a specific monoclonal antibody (MAb 114/2).

Human fetal and adult liver metabolism of ethylmorphine. Relation to immunodetected cytochrome P-450 PCN and interactions with important fetal corticosteroids.

The N-demethylation of ethylmorphine was studied in liver microsomes from human fetuses and adult patients as well as from human fetal adrenals and kidneys. Unexpectedly the reaction was catalysed at the same rate in fetal (42.3-1277.

Monoclonal antibody directed detection of cytochrome P-450 (PCN) in human fetal liver.

Monoclonal antibodies (MAbs) raised to rat liver cytochrome P-450s induced by phenobarbital, 3-methylcholanthrene, and pregnenolone-16 alpha-carbonitrile were used to detect these epitope specific P-450s in human abortion fetuses 14-24 weeks of age. This was performed using a Western blot technique. In parallel, ECOD was determined in the same tissue specimens.

Dihydropyridine modulation of the chromaffin cell secretory response.

Prolonged perfusion of cat adrenal glands with Krebs-bicarbonate solutions containing nicotine, muscarine, or excess K rapidly increased the rate of catecholamine output proportional to the concentrations of secretagogue used. The secretory responses to nicotine or high K reached a peak and declined to almost basal rates of secretion after about 10 min of stimulation. The dihydropyridine Ca channel agonist Bay K 8644 potentiated markedly the secretory responses to 1 microM nicotine and to 17.

Influence of hypertonic solutions on catecholamine release from intact and permeabilized cultured chromaffin cells.

Chromaffin cells purified from bovine adrenal medulla and maintained in primary culture were used to study the effects of hyperosmolarity on the nicotine- and high potassium-induced secretory response. A similar study was also performed on cells permeabilized with digitonin and with alpha-toxin from Staphylococcus aureus. Hyperosmolarity does not affect the spontaneous release of catecholamines from either intact cells or permeabilized cells.

Effects of hypertonic solutions on catecholamine release from cat adrenal glands.

The effects of hypertonic solutions on the spontaneous and evoked catecholamine release from isolated, perfused cat adrenal glands were studied. Hypertonic solutions enhanced three times the spontaneous release of the amines, but markedly inhibited the release evoked by nicotine (5 microM for 2 min) or high K+ (17.7 mM for 2 min).