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Biomedical subjects

J M Morsman

Publications and source records attributed to J M Morsman.

12 recordsLinked to original sources
PubMed2001

Human CYP1B1 and anticancer agent metabolism: mechanism for tumor-specific drug inactivation?

The cytochrome P450 1B1 (CYP1B1) is involved in the metabolism of procarcinogens and xenobiotics. Human CYP1B1 protein has been detected in a variety of tumors but is not detected in adjacent normal tissues or in liver. This suggests that CYP1B1 could biotransform anticancer agents specifically in the target cells. The interaction between CYP1B1 and 12 commonly used anticancer drugs was screened using an ethoxyresorufin deethylase assay. Four agents were competitive inhibitors of CYP1B1 activity: flutamide (K(i) = 1.0 microM), paclitaxel (K(i) = 31.6 microM), mitoxantrone (K(i) = 11.6 microM), and docetaxel (K(i) = 28.0 microM). Doxorubicin (K(i) = 2.6 microM) and daunomycin (K(i) = 2.1 microM) were mixed inhibitors, while tamoxifen was a noncompetitive inhibitor (K(i) = 5.0 microM). Vinblastine, vincristine, 5-fluorouracil, etoposide, and cyclophosphamide did not inhibit CYP1B1 activity. In vitro incubations with flutamide and CYP1B1 produced a metabolite consistent with 2-hydroxyflutamide. Comparison of kinetic parameters (K(m), K(i), V(max)) for flutamide 2-hydroxylation by CYP1B1, CYP1A1, and CYP1A2 indicate that CYP1B1 could play a major role for flutamide biotransformation in tumors. The results obtained indicate that several anticancer agents inhibit CYP1B1 activity. Drug inactivation by CYP1B1 may represent a novel mechanism of resistance, influencing the clinical outcome of chemotherapy.

Antineoplastic Agents↗
PubMed2000

Evaluation of dihydropyrimidine dehydrogenase activity in South-west Asian, Kenyan and Ghanaian populations.

AIMS: Dihydropyrimidine dehydrogenase (DPD) reduces endogenous pyrimidines and therapeutic analogues such as the anticancer agent 5-fluorouracil (5FU). Among Caucasian populations DPD activity is highly variable and subject to polymorphic regulation. To evaluate interethnic influence, DPD activity was assessed in South-west Asian, Kenyan and Ghanaian populations. METHODS: DPD activity was determined in peripheral mononuclear cells using[14C]-5-fluorouracil and h.p.l.c. analysis. RESULTS: A high degree of variation in DPD activity was observed within each population (range CV = 34-48%). Median DPD activity also varied between these populations. South-west Asian and Kenyan subjects exhibited almost identical median values (192 and 193.5 pmol min(-1) mg(-1), respectively), which were similar to Caucasians (median 215 pmol min(-1) mg(-1). A significantly lower median DPD activity (119 pmol min(-1) mg(-1)) was observed in the Ghanaian population. CONCLUSIONS: The similarity in DPD activity between Caucasian, Kenyan and South-west Asian populations suggests that the incidence of 5FU-related toxicity may be comparable in these groups. The pharmacokinetic implications of lower activity amongst Ghanaians needs to be evaluated.

Adult↗
PubMed1984

The use of cloned Y chromosome-specific DNA probes for fetal sex determination in first trimester prenatal diagnosis.

Prenatal diagnosis by chorion biopsy in the first trimester of pregnancy has advantages over second trimester amniocentesis because diagnosis can be achieved at 9-12 weeks gestation, reducing prenatal anxiety and avoiding the trauma of late abortion. DNA can be prepared from chorionic villus biopsies in sufficient quantity and purity for use in prenatal diagnosis systems using specific DNA probes hybridised to restriction endonuclease digests. DNA probes derived from the Y chromosome have been used to determine fetal sex. The use of such probes means that the chromosomal sex of the fetus can be identified more quickly than by chromosome preparation and more accurately than by sex chromatin staining, and has the additional advantage that the same DNA preparation can be used for other diagnostic tests. A dot hybridisation method has been successfully used to provide even more rapid results than conventional hybridisation to Southern blots of restriction endonuclease digests. There is a risk that Y chromosome-specific DNA probes for sex determination may be subject to error if the parents have extreme Y chromosome variants such as a small or non-fluorescent Y or a Y autosome chromosome translocation. The precise extent to which such chromosome variants may lead to error has been investigated. Even extreme Y chromosome variants totally lacking fluorescence were identified as male by the cloned probes used. However, Y autosome translocations carried by females could cause error if not identified in the parents. The value of the probes has been confirmed provided that parental chromosomes and DNA are examined in parallel with the chorionic biopsy material.

Cloning, Molecular↗
PubMed1982

Direct vision chorion biopsy and chromosome-specific DNA probes for determination of fetal sex in first-trimester prenatal diagnosis.

Fetal sex was determined prenatally by molecular analysis of DNA from chorionic biopsy specimens taken in the first trimester of pregnancy. Single villi were obtained transcervically under direct vision with ultrasound guidance. The results of restriction endonuclease analysis of Y-chromosome-specific DNA from the biopsy specimens of 13 patients were confirmed in all cases by fetal karyotype analysis of cultures of biopsy specimens taken in parallel and of cultures of the products of conception. Prenatal sex determination by this method takes only 3-4 days and is not subject to the same errors as F-body identification.

Adolescent↗