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Biomedical subjects

J R Idle

Publications and source records attributed to J R Idle.

At least 127 records · Page 7Linked to original sources
PubMed1989

Cytochrome P450IID phenotypes and human cancer risk.

This paper reviews the work carried out by the author and his colleagues which has sought to determine the relative risk of various cancers and related conditions in extensive (EM) and poor (PM) metabolizer phenotypes which arise from the P450IID-mediated 4-hydroxylation of debrisoquine. Sex, phenotype, and occupation all markedly influence the relative risk of lung tumors in smokers, the last two of which demonstrate a powerful interaction. Future studies will need to be large and to use molecular and/or immunocytochemical approaches.

Abdominal Neoplasms↗
PubMed1988

Phenotypically deficient urinary elimination of carboxyphosphamide after cyclophosphamide administration to cancer patients.

The 0-24-h urinary metabolic profile of cyclophosphamide was investigated in a series of 14 patients with various malignancies receiving combination chemotherapy including i.v. cyclophosphamide. This was accomplished using combined thin-layer chromatography-photography-densitometry, which can quantitate cyclophosphamide and its four principal urinary metabolites (4-ketocyclophosphamide, nor-nitrogen mustard, carboxyphosphamide, and phosphoramide mustard). Recovery of drug-related metabolites was 36.5 +/- 17.8% (SD) dose, the most abundant metabolites being phosphoramide mustard (18.5 +/- 16.1% dose) and unchanged cyclophosphamide (12.7 +/- 9.3% dose). The most variable metabolite was carboxyphosphamide, with five patients excreting 0.3% dose or less. These patients were termed low carboxylators (LC) and could be distinguished from high carboxylators (HC) by a carboxylation index (relative percentage as carboxyphosphamide multiplied by 10). Mean carboxylation indices for the LC and HC phenotypes were 3.4 +/- 2.6 and 151 +/- 115, respectively. There were no associations between patient age, sex, body weight, tumor type, or concomitant drug therapy and carboxylation phenotype. Neither 4-ketocyclophosphamide nor nor-nitrogen mustard excretion differed between LC and HC phenotypes; however, HC patients had a greater excretion of cyclophosphamide (46.4 +/- 15.5 relative percentage) than LC patients (19.4 +/- 12.6%). The DNA cross-linking cytotoxic metabolite phosphoramide mustard was elevated more than 2-fold in the LC (76.5 +/- 13.9%) compared with the HC (33.0 +/- 12.2%) phenotype. It is concluded that these data represent the first evidence of a defect in cyclophosphamide metabolism, and it is proposed that this arises from a hitherto unrecognized aldehyde dehydrogenase genotype.

Adult↗
PubMed1988

Combined thin-layer chromatography-photography-densitometry for the quantitation of cyclophosphamide and its four principal urinary metabolites.

A novel method for the quantitative determination of the anti-cancer drug cyclophosphamide and its principal urinary metabolites 4-oxocyclophosphamide, carboxyphosphamide, phosphoramide mustard and bis(2-chloroethyl)amine has been devised. The assay combines adsorption of drug-related material onto Amberlite XAD-2 and thin-layer chromatography with spot visualization using 4-(4-nitrobenzyl)pyridine, rapid photography and densitometry. The intra-assay coefficient of variation for each compound was less than 6%. The limit of detection of the assay was 1 microgram ml-1 for cyclophosphamide, phosphoramide mustard and bis(2-chloroethyl)amine and 0.5 microgram ml-1 for 4-oxocyclophosphamide and carboxyphosphamide. The method was validated for cyclophosphamide and 4-oxocyclophosphamide using gas chromatography. It is concluded that the method provides the first means of determining the full metabolic spectrum for cyclophosphamide in patients without recourse to the administration of radioisotopically labelled drug.

Biotransformation↗
PubMed1988

Determination of nifedipine and its three principal metabolites in plasma and urine by automated electron-capture capillary gas chromatography.

A sensitive, efficient, linear and reproducible capillary gas chromatographic method with electron-capture detection was developed for the quantitation of nifedipine and its primary metabolite M-I in plasma together with the urinary and principal metabolites M-II and M-III. On-column, rather than split-splitless, injection was employed to obviate oxidative degradation of nifedipine to M-I. The photosensitivity of nifedipine was re-examined under laboratory conditions and nifedipine was found to have a half-life in excess of two days when amber glassware and darkroom manipulations under red light were used. The method can determine nifedipine and its metabolites in plasma and urine after a single oral dose of 5 mg and can be applied to measure M-I production by human liver microsomes.

Autoanalysis↗
PubMed1988

Trimethylaminuria ('fish-odour syndrome'): a study of an affected family.

1. Beginning with a single propositus, who had been previously diagnosed at the age of 10 as suffering from trimethylaminuria (fish-odour syndrome), both her parents and two sisters were investigated biochemically with respect to their ability to N-oxidize trimethylamine (TMA), both when derived from the diet and when administered exogenously. 2. Both the propositus and a second sister were markedly deficient in their ability to N-oxidize TMA, both when derived from the diet and when given as such; furthermore, both siblings readily developed the symptoms of fish-odour syndrome as characterized by a strong objectionable breath and body odour shortly after the oral administration of TMA (300 mg). 3. At this dose level of TMA, neither of the parents nor the third sister showed any evidence of impaired N-oxidation ability nor did they experience any 'fish-odour' symptoms. 4. With an oral challenge of 600 mg of TMA, both the parents showed a clear impairment of N-oxidation capacity which was not seen in six healthy unrelated volunteers. Both parents experienced a fish-odour syndrome at this level of TMA challenge. 5. The family data support the hypothesis that trimethylaminuria is an inborn error in the ability to N-oxidize TMA which is inherited as an autosomal recessive trait. Furthermore, experience with this family suggests that an oral challenge dose with 600 mg of TMA may be used to identify carriers of the condition.

Adult↗
PubMed1988

Human P450PCN1: sequence, chromosome localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase.

P450PCN protein levels and nifedipine oxidase activities were quantitated in 12 human livers and were shown to be highly correlated. Antibody against rat P450PCN1 completely inhibited all nifedipine oxidase activity in three human liver samples. These results suggest that a human P450 related to rat P450PCN1 is the major form of P450 catalyzing nifedipine oxidation. The cDNA for a human P450, designated phPCN1, was isolated from a human liver lambda gt11 cDNA library, and sequenced completely. The deduced amino acid sequence is 77% similar to rat P450PCN1. By use of the adenovirus- and SV40-based expression vecotr p91023(B), the phP450PCN1 cDNA was expressed in COS cells and had high nifedipine oxidase activity, providing conclusive evidence that this P450 is the primary enzyme associated with metabolism and inactivation of this important drug. Using somatic cell hybrids, the P450PCN gene was localized to human chromosome 7.

Amino Acid Sequence↗
PubMed1988

Glutathione transferase activities of cultured human lymphocytes.

We have detected glutathione transferase (GST) activity towards 1-chloro-2,4-dinitrobenzene (CDNB) and benzo[a]-pyrene 4,5-oxide (BPO) in freshly isolated peripheral lymphocytes, phytohaemagglutinin (PHA)-stimulated lymphocytes, interleukin-2 (IL-2)-dependent T-cells and lymphoblastoid B-cell lines. The detection of conjugating activity with BPO implies the expression of a neutral, 'mu-like' GST form by both resting and cultured lymphocytes. In a sample of 12 unrelated individuals, BPO conjugating activity of freshly isolated lymphocytes showed a polymorphic distribution. In comparison with freshly isolated cells, BPO activity was increased 2- to 5-fold in IL-2-dependent T-cells and 4- to 10-fold in B-cell lines. The CDNB activity of T-cells was not significantly different to that of freshly isolated cells (P greater than 0.05) but activity in B-cell lines showed a significant increase (P less than 0.01). These data indicate that measurement of BPO activity in freshly isolated lymphocytes may allow the study of the human GST-mu polymorphism. However, IL-2-dependent culture of T-cells or viral immortalization of resting lymphocytes appears to cause the activation or induction of a GST form or forms which conjugate BPO efficiently. In the T-cells this effect may be mediated through addition of IL-2 to the culture since PHA treatment alone did not elevate activity.

Benzopyrenes↗
PubMed1988

The gene CYP3 encoding P450pcn1 (nifedipine oxidase) is tightly linked to the gene COL1A2 encoding collagen type 1 alpha on 7q21-q22.1.

CYP3, the gene which encodes the hepatic cytochrome P450pcn1, the isozyme responsible for the metabolic oxidation of the calcium channel-blocking drug nifedipine, has recently been mapped to human chromosome 7 using somatic cell hybrids. Using multilocus linkage analysis in CEPH families, we examined the linkage of a cDNA probe (hPCN1) for CYP3 to the oncogene MET, the pro-alpha 2(1) collagen gene COL1A2, and the T-cell receptor beta-chain gene TCRB, together with three arbitrary loci D7S8, D7S13, and D7S16, defined by the anonymous DNA probes pJ3.11, pB79a, and p7C22, respectively. From 70 CEPH parents screened with a StyI RFLP for hPCN1, four informative families were found each with both parental and maternal grandparents and 6-11 children per family. Tight linkage emerged between CYP3 and COL1A2, with a maximum combined lod score of 5.72 at theta = 0, suggesting the most likely subchromosomal localization of CYP3 is 7q21.3-q22.1.

Chromosomes, Human, Pair 7↗
PubMed1987

A genetic polymorphism of the N-oxidation of trimethylamine in humans.

Trimethylamine (TMA) and its N-oxide (TMAO) are normal components of human urine. They are present in the diet and also derived from the enterobacterial metabolism of precursors such as choline. Dietary TMA is almost entirely metabolized to and excreted as TMAO. However, the extent to which TMA undergoes N-oxidation appears to be polymorphic in a British white population study (n = 169). Two propositi were identified with relative TMA N-oxidation deficiency that was further confirmed by oral challenge with TMA (600 mg). The study of the families of the two propositi, as well as those of two identified subjects with trimethylaminuria, under both normal dietary conditions and after oral TMA challenge strongly indicates that the conditions of impaired N-oxidation is inherited as a recessive trait. It is proposed that the N-oxidation of TMA in humans is polymorphic and under single gene diallelic control in which individuals who are homozygous for the variant allele exhibit marked N-oxidation deficiency and trimethylaminuria.

Adolescent↗
PubMed1987

Disclosure of the metabolic retroversion of trimethylamine N-oxide in humans: a pharmacogenetic approach.

Trimethylamine N-oxide (TMAO), which is naturally occurring in dietary marine fish, is well absorbed and excreted apparently unchanged as judged by end-product analysis. Such observations may conceal the fact that the amine N-oxide has undergone a sequence of deoxygenation and oxygenation reactions only to revert to the parental form and be excreted as such--a process that we propose to call metabolic retroversion. To evaluate this phenomenon for TMAO we have investigated the fate of the orally administered substance in healthy volunteers and in four subjects previously phenotyped as having an inherited deficiency with respect to the metabolic N-oxidation of trimethylamine (TMA). Two of these subjects were typed as homozygous affected and the other two as "carriers." If substantial reduction of orally administered TMAO occurs during the course of its postulated retroverted metabolism, it was hypothesized that this would be revealed by the extensive urinary excretion of unoxidized TMA by the four affected subjects. After oral TMAO administration in the four healthy subjects, greater than 94% of the urinary TMA was in the form of TMAO and only less than 4% as the free base. However, after oral TMAO in the two homozygous-affected subjects, unoxidized TMA accounted for 35% and 51%, respectively, of the total urinary TMA, the balance being due to TMAO. For the carrier subjects, TMA accounted for 12% and 16% of the total urinary TMA after TMAO administration. It is thus clear that the urinary excretion of unoxidized TMA is increased greatly in affected subjects with an inherited deficiency of N-oxidation after the oral administration of TMAO.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1987

The metabolism of 14C-labelled trimethylamine and its N-oxide in man.

The metabolism and elimination of 14C-labelled trimethylamine and its N-oxide (100 mg orally) were studied in three male volunteers. For both compounds the urine was the major route of elimination, with 95% of the administered 14C being voided in the first 24 h. No radioactivity was found in expired air. The majority (greater than 95%) of the urinary 14C from both compounds was excreted as trimethylamine N-oxide.

Biotransformation↗
PubMed1986

Sulphoxidation of S-carboxymethyl-L-cysteine in the rhesus monkey (Macaca mulatta), cynomologus monkey (Macaca fascicularis), African green monkey (Cercopithecus aethiops) and the marmoset (Callithrix jacchus).

The metabolic pathways giving rise to the urinary metabolites of S-carboxymethyl-L-cysteine have been identified for the rhesus, cynomologus, African green and marmoset species of monkey. The formation of a sulphoxide metabolite from the sulphide precursor is a reaction important in these species. The metabolic profile displayed by the marmoset was distinct from the three Old World species, with the rhesus and cynomologus being similar to man.

Animals↗
PubMed1986

The metabolism of debrisoquine in man: (1) regioselectivity of hydroxylation and (2) aberrant oxidative metabolism in two sibling patients with carbimazole-induced agranulocytosis.

The regioselectivity of the metabolic hydroxylation of debrisoquine has been determined in 43 healthy British white volunteers and the priority was found to be in the order 4 greater than 7 greater than 6 greater than 5 greater than 8. The order of preference for hydroxylation position was independent of debrisoquine 4-hydroxylation phenotype. The extent of total aromatic hydroxylation varied widely between individuals and was largely independent of the extent of 4-hydroxylation, and thus of the influence of the DH/DL locus. Two sisters and their blood relations all excreted comparatively large amounts of the phenolic metabolites in their urine, indicating some genetic basis for the control of aromatic oxidation of debrisoquine in man. These same two sisters had previously developed agranulocytosis in association with carbimazole therapy.

Adolescent↗
PubMed1985

Dissociation of co-regulatory control of debrisoquin/phenformin and sparteine oxidation in Ghanaians.

The ability to oxidize sparteine to form 2- and 5-dehydrosparteine was studied in 154 healthy Ghanaians. Although the urinary metabolic sparteine/dehydrosparteines ratio varied widely (from 0.14 to 12.5), in contrast to observations in several Caucasian population groups the ratios were not bimodally distributed and no phenotypically poor oxidizers of sparteine were found. The ability of these same subjects to oxidize debrisoquin and phenformin was also studied in 141 and 143 subjects. Of the 141 subjects dosed with debrisoquin, 10 proved to be poor oxidizers, and of the 143 subjects dosed with phenformin, 11 were poor oxidizers. All the poor oxidizers of debrisoquin were also poor oxidizers of phenformin. The 10 confirmed poor metabolizers of debrisoquin, who had debrisoquin metabolic ratios ranging from 14.4 to 52.0, had sparteine metabolic ratios ranging only from 0.15 to 12.5. Whereas Caucasian poor metabolizers of sparteine excrete less than 2.0% of a dose as dehydrosparteines, the mean excretion of dehydrosparteines in our 10 subjects was 20.6% +/- 13.2%. The overall rank correlation between the sparteine and debrisoquin metabolic ratios was low (rs = 0.47), while the coefficient of determination for linear regression (r2) was only 0.17. Our data show that the ability of Ghanaians to oxidize sparteine is largely independent of their capacity for debrisoquin oxidation and is indicative of a major interethnic difference in the genetic control of these reactions.

Administration, Oral↗