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Biomedical subjects

C L Wright

Publications and source records attributed to C L Wright.

At least 19 recordsLinked to original sources
PubMed1992

Metabolism of 11-deoxycorticosterone by hamster adrenal mitochondria.

Metabolism of 11-deoxycorticosterone (DOC) by hamster adrenal mitochondria gives 19-hydroxy-DOC and corticosterone (via 11-hydroxylation) in approximately equal yields. The ratio of 19- to 11-hydroxylation was invariant with changes in concentration of substrate or a competitive inhibitor. It is most likely, therefore, that a single 11,19-hydroxylase catalyzes both oxidations. Both primary products are further oxidized to the corresponding carbonyl analogs, 19-oxo-DOC and 11-dehydrocorticosterone, at rates that are approx. 20% of their rates of formation. The oxidation of 11-dehydrocorticosterone is catalyzed by a dehydrogenase utilizing either NAD or NADP while the oxidation of 19-hydroxy-DOC is catalyzed by an oxidase requiring NADPH. The 11-dehydrocorticosterone is stable in this enzyme preparation while 19-oxo-DOC is metabolized to two additional products, which are tentatively identified as 19-oic-DOC and 19-norcorticosterone. 19-nor-DOC was found to be hydroxylated at a rate that is 20% faster than the rate for DOC under the same conditions. It is therefore possible that 19-norcorticosterone can arise from 19-oic-DOC via decarboxylation to 19-nor-DOC and subsequent 11-hydroxylation, but the kinetics of its formation suggest that it may actually be formed directly from 19-oxo-DOC without free intermediates. 4-Androstene-3,17-dione and 17-hydroxy-DOC were also substrates for this 11,19-hydroxylase, but 18-hydroxy-DOC was not. Maintenance of hamsters on a low sodium diet had no effect on the metabolism of DOC by the isolated adrenal mitochondria.

Adrenal Glands↗
PubMed1991

Regioselectivity of metabolic activation of acetylenic steroids by hepatic cytochrome P450 isozymes.

Liver cytochrome P450 monooxygenases (P450), a group of isozymes that catalyze the reductive cleavage of molecular oxygen, dominate hepatic metabolism of xenobiotic lipophilic substances. These P450 enzymes exhibit broad and overlapping substrate specificities, in contrast to the P450 isozymes of the steroid biosynthetic pathways, which are highly substrate specific. Hepatic heme pigments, N-alkylated porphyrins, accumulate following the self-catalyzed destruction of P450 by the metabolic activation of 17 alpha-ethynyl steroids. Acetylenic substituted steroidal aromatase inactivators, norethisterone (NET), and 10-(2-propynyl)estr-4-ene-3,17-dione (MDL 18,962) were administered to rats to determine if the acetylenic substituent was activated by hepatic P450 mixed-function oxidases. This metabolism could result in the formation of a reactive species that would alkylate a pyrrole nitrogen atom of heme. Male Sprague-Dawley rats were treated with 0, 10, 30, or 100 mg/kg NET or MDL 18,962 intraperitoneally. Four hours later, these animals received 40 mg/kg sodium pentobarbital and their sleeping times were recorded. On arousal, the rats were killed and their livers were taken for determination of P450 content and formation of N-alkylated porphyrins (green pigments). Norethisterone inhibited hepatic P450 isozymes, resulting in a dose-related increased sleeping time (89.2 +/- 3.5 to 156.3 +/- 7.6 minutes) and decreased P450 levels (maximum 25% decrease at 100 mg/kg), and the amount of green pigments increased with doses of 10 to 100 mg/kg. In contrast, MDL 18,962 treatment did not increase sleeping time and caused only a 15% decrease in hepatic P450 content at 100 mg/kg, with no detectable green pigments.(ABSTRACT TRUNCATED AT 250 WORDS)

Androstenedione↗
PubMed1990

Enzyme inactivation by potential metabolites of an aromatase-activated inhibitor (MDL 18,962).

MDL 18,962, 19-acetylenic androstenedione, is an enzyme-activated inhibitor of estrogen biosynthesis which is in Phase I clinical evaluations as a potential therapeutic agent for estrogen-dependent cancers. 19-Acetylenic analogs corresponding to the major metabolites of androstenedione were synthesized as potential metabolites of MDL 18,962. These compounds were 19-acetylenic testosterone, the product of 17 beta-hydroxy steroid oxidoreductase, 6 beta-hydroxy- and 6-oxo-19-acetylenic androstenedione, products of P450 steroid 6 beta-hydroxylase and alcohol dehydrogenase, respectively. All of these analogs showed time-dependent inactivation of human placental aromatase activity. The time-dependent Ki and t1/2 at infinite inhibitor concentration (tau 50) were 4.3 nM, 12.0 min for MDL 18,962; 28 nM, 7.8 min for 17-hydroxy analog; 13 nM, 37 min for 6 beta-hydroxy analog; and 167 nM, 6.1 min for the 6-oxo analog. The 19-acetylenic testosterone, a confirmed metabolite from primate studies, was 25% as efficient as MDL 18,962 for aromatase inactivation, while 6 beta-hydroxy- and 6-oxo analogs were 11% and 5%, respectively as efficient as their parent compound. These data indicate that first-pass metabolism of MDL 18,962 does not cause an obligatory loss of time-dependent inhibition of human aromatase activity.

Androstenedione↗
PubMed1989

Human trophoblast xenografts in athymic mice: a model for peripheral aromatization.

A novel procedure was developed for evaluating aromatase inhibitors using human enzyme in a rodent model. Human choriocarcinoma trophoblast (JAr line) cells injected subcutaneously into athymic nude mice develop into tumor xenografts in 7-14 days which represent sites for peripheral aromatization of androgens. The rapid growth of these trophoblast tumors is estrogen independent. The tumors provide a source of nonovarian human tissue which has relatively high levels of enzyme activity (248 +/- 12 pmol estrogen/g/h) for biochemical determination of in vivo aromatase inhibition. These are major advantages for pharmacological evaluations in comparison to the slow tumor growth response of most carcinogen-induced rodent mammary cancers, which are usually devoid of aromatase activity. In addition, the hormonal dependent components of rodent mammary tumors require several weeks to regress as a result of the indirect effects of estrogen deprivation on tumor growth via inhibition of prolactin dependency, a minor component relative to the role estrogen occupies in hormonally-dependent breast cancer in humans. This model of peripheral aromatization was utilized to evaluate in vivo pharmacological parameters of MDL 18,962 (10-(2-propynyl)estr-4-ene-3,17-dione) such as bioavailability of several formulations, time course and dose responses following different routes of drug administration, pharmacokinetics and tissue distribution of [14C]MDL 18,962. Tumor aromatase activities of trophoblast xenografts were significantly (P less than or equal to 0.05) inhibited when MDL 18,962 was administered intravenously, orally, subcutaneously, or via subcutaneous silastic implants. The ED50 of MDL 18,962 for tumor aromatase inhibition at 6 h after a single treatment was 1.4 mg/kg, s.c. and 3.0 mg/kg, orally. MDL 18,962 blocked aromatase activity more effectively in human trophoblast than in mouse ovarian tissue. Human trophoblast aromatase activity was inhibited by 70% following a single oral dose of 100 mg/kg of MDL 18,962, while the host's ovarian aromatase activity exhibited only marginal inhibition. In vitro, the addition of 10 microM MDL 18,962 to trophoblast tumor cytosol or mouse ovarian cytosol resulted in 99.6 and 91.4% inhibition of aromatase activity, respectively. Tissue distribution of [14C]MDL 18,962 was predominantly associated with endocrine tissues with aromatase activity and organ systems involved in steroid metabolism and excretion. These in vivo data show that MDL 18,962 an enzyme-activated aromatase inhibitor, causes prolonged aromatase inhibition in the absence of saturating levels of inhibitor.

Androstenedione↗
PubMed1988

A survey of fourth-year medical students' decisions regarding family practice as a career.

With a decline in the proportion of medical students pursuing family practice careers, it is necessary to better understand the factors influencing their career decisions. The Fishbein model of attitude formation was used as a framework for developing a questionnaire to measure students' attitudes toward a career in family practice and the social support students perceived they had for that career. The questionnaire was administered to fourth-year-medical students a short time before residency match day. Both the attitude and social support scales had excellent psychometric characteristics. The usefulness of these scales in discriminating between career choices of family practice and other clinical careers was tested. The social support scale did not discriminate well, whereas the attitude scale discriminated quite well. The students who chose careers in family practice differed from students who chose other careers in 14 of 19 values about characteristics of family practice but differed from them in only two of 19 beliefs about family practice. The implications for advising medical students about careers in family practice are discussed.

Attitude↗
PubMed1987

Inhibition of human monocyte antigen presentation, but not HLA-DR expression, by cyclosporine.

The effects of cyclosporine (CsA) on antigen-dependent human T cell proliferation have been studied using tetanus toxoid as the antigen. CsA significantly inhibited antigen-dependent T cell proliferation at concentrations as low as 0.1 microgram/ml. In dissecting this system we found that preexposure of separated monocytes to CsA during the period of antigen processing led to a marked inhibition of proliferation of T cells added subsequently to the monocytes. We investigated whether this suppressive effect on monocyte antigen presentation was related to monocyte HLA-DR expression, interleukin 1 (IL-1) production, or prostaglandin (PG) secretion. None of these functions seemed to be affected by CsA. In particular, human monocyte HLA-DR expression was not inhibited by CsA, even at concentration of 10 micrograms/ml. The addition of exogenous IL-1 or indomethacin did not reverse the inhibitory effects of CsA. These experiments demonstrate that CsA inhibits antigen-dependent human T cell proliferation, at least in part by acting directly on human monocytes to inhibit antigen presentation. The mechanism of action seems to be independent of IL-1 production, PG secretion, and HLA-DR expression.

Antigen-Presenting Cells↗
PubMed1987

Rising malpractice premiums and obstetric practice patterns. The impact on family physicians in Washington State.

All 853 active members of the Washington Academy of Family Practice were surveyed in the summer of 1985 to determine the impact of rising malpractice premiums on patterns of obstetric practice. Of the 685 physicians who responded, 61% are currently practicing obstetrics. The median number of deliveries per year was 29, with a range of 1 to 130 deliveries per physician. Younger physicians, rural physicians and those in group practice were more likely to practice obstetrics than older, urban physicians in solo practice. Of the 266 respondents not currently practicing obstetrics, 77% had discontinued obstetric practice within the past five years-half because of issues related to professional liability. Of those practicing obstetrics, 50% stated that they would cease obstetric practice if malpractice premiums rose to $12,000.

Costs and Cost Analysis↗
PubMed1986

Pharmacological induction of 5 alpha-reductase deficiency in the rat: separation of testosterone-mediated and 5 alpha-dihydrotestosterone-mediated effects.

(5 alpha, 20S)-4-Diazo-21-hydroxy-20-methylpregnan-3-one, a mechanism-based inhibitor of testosterone 5 alpha-reductase, produced pronounced and long lasting inhibition of the enzyme in the prostate and preputial glands when administered orally to rats. Administration of the inhibitor to castrate rats bearing testosterone implants produced inhibition of growth of the prostate, seminal vesicles,and preputial glands, but had no effect on growth of the levator ani muscle. (5 alpha-20S)-4-Diazo-21-hydroxy-20-methylpregnan-3-one did not antagonize growth of the accessory sex organs induced by 5 alpha-dihydrotestosterone (5 alpha-DHT). The inhibitor thus produced a pure 5 alpha-reductase deficiency in the rat without detectable receptor-level antagonism, and with consequences similar to those occurring at puberty in the 5 alpha-reductase-deficient human male: reduction of 5 alpha-DHT-mediated processes and maintenance of those mediated by testosterone. The results emphasize the importance of the enzymatic profiles of individual organs in determining selective response to testosterone or 5 alpha-DHT. Evidence is presented which indicates that the testes are the source of circulating 5 alpha-DHT in the immature rat.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1986

Synergy between interleukin-2 and a second factor in the long-term growth of human T cells.

It has recently been shown that factors in addition to interleukin-2 (IL-2) are required for the proliferation or differentiation of at least some murine T-cell lines. We have previously shown that conditioned medium from human mononuclear cells stimulated with phorbol ester and staphylococcal enterotoxin A is superior to commercial sources of IL-2 for the long-term growth of human T cells. We have identified in these supernatants a non-IL-2 factor (synergistic factor, SF) which synergizes with JURKAT IL-2 in the long-term growth of human T cells. [3H]TdR incorporation by IL-2-dependent human T cells after growth in IL-2 or SF alone for 14 days was slight, but significant. By contrast, growth in a combination of SF and IL-2 for 14 days stimulated [3H]TdR incorporation 10-20-fold higher, generally equal to the high incorporation measured when cells were grown in the presence of the conditioned medium from which SF was obtained. In a standard 2-day IL-2 assay, there was no correlation between activity and long-term growth-promoting ability. These results suggest that the 14-day assay better discerns the growth-promoting activity of various factors or combinations of factors. The mechanism of this interaction between SF and IL-2 remains to be elucidated. It is clear, however, that T-cell growth factor activity, when assessed by the long-term growth of human T cells, is not due to interleukin-2 alone.

Antigens, Surface↗
PubMed1985

The adjuvant effects of mycoviral dsRNA and polyinosinic:polycytidylic acid on the murine immune response.

By comparing, under the same experimental conditions, the effects of naturally occurring mycoviral dsRNA with those of the synthetic dsRNA, polyinosinic:polycytidylic acid, we were able to determine if the source of the dsRNA would modify its immunomodulating properties. Mycoviral dsRNA, but not the synthetic dsRNA, significantly enhanced the hemagglutinating antibody response to sRBC in C57B1/6 mice. Although both dsRNA preparations significantly increased the rate of rejection of heterologous skin grafts by recipient mice when compared to controls, mycoviral dsRNA induced higher interferon titers than the synthetic dsRNA. This study showed that mycoviral dsRNA was a more potent adjuvant than polyinosinic:polycytidylic acid for both humoral and cellular immune responses.

Adjuvants, Immunologic↗
PubMed1985

Degeneration of the rat and canine adrenal cortex caused by alpha-(1,4-dioxido-3-methylquinoxalin-2-yl)-N-methylnitrone (DMNM).

The antibacterial drug alpha-(1,4-dioxido-3-methylquinoxalin-2-yl) N-methylnitrone (DMNM) given at a dose of 22.5 mg/kg bid to four dogs for 14 days caused diminished adrenal cortical reserves as determined by decreased plasma cortisol (three dogs) and lower aldosterone levels (four dogs) following the intravenous infusion of ACTH. A dose of 100 mg/kg/day of DMNM administered to rats for 31 or 35 days resulted in significant decreases in blood glucose. Histologically, the adrenal glands of both species treated with DMNM for a maximum period of 21 days (dogs) and 35 days (rats) had widespread granular and vacuolar degeneration of the cortex. This degeneration in treated rats began in the zona reticularis and inner regions of the zona fasciculata and eventually involved the entire cortex including the zona glomerulosa. As a result of treatment, significant ultrastructural alterations within cells of the rat and canine adrenal cortex consisted of degeneration of the mitochondria and an increase in the numbers and lipolysis of lipid droplets. The ultrastructure of the zona reticularis and fasciculata was most severely affected.

Adrenal Cortex↗