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Results for “Cytochrome P-450 CYP2C8”

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PubMed1976

Aryl hydrocarbon hydroxylase and 16alpha-hydroxylase in cultured human lymphocytes.

Aryl hydrocarbon hydroxylase and 16alpha-hydroxylase were examined in intact, cultured human lymphocytes. The two microsomal mixed-function oxygenases had different pH optima and showed competitive inhibition for enzyme induction and activity. Population distributions were lognormal for both enzymes, giving apparent evidence for polygenic control. Induced levels of AHH were slightly higher among first-order relatives of lung or colon cancer patients than in the control group. The correlation coefficient (r) for AHH and SAH coinducibility was -0.08, indicating no correlation and suggesting the absence of association between the two enzymes in man.

Aryl Hydrocarbon Hydroxylases↗

PubMed1976

The pattern and rates of metabolism of maternal plasma dehydroisoandrosterone sulfate in human pregnancy.

The present study was done to map the metabolic pathways and rates of maternal plasma clearance of dehydroisoandrosterone sulfate (MCRDS) in pregnancy. In the present study, maternal plasma dehydroisoandrosterone sulfate (DS) metabolism was largely accounted for by two major pathways not present or not prominent in the nonpregnant woman. The first major pathway was clearance of maternal plasma DS by placental aromatization of DS to form estradiol (E2). This pathway accounted for approximately 35 per cent of the total clearance. The second major pathway of metabolism of maternal plasma DS was by 16 alpha-hydroxylation within the maternal compartment. This pathway accounted for approximately 32 per cent of maternal plasma DS clearance. Two other minor pathways of DS metabolism, that is, loss to the fetus and excretion as unaltered DS into urine, accounted for less than 1 per cent of total metabolism in each instance. The final pathway of DS metabolism was excretion as neutral steroids such as urinary 17-ketosteroids and other undefined losses. By combining the rate of DS clearance (MCRDS) from maternal plasma via all pathways with that fraction of DS removed uniquely by placental conversion of DS to estradiol (DS leads to E2), the placental clearance of DS leads to E2 (PCDSE2) may be measured. The measurement of PCDSE2 may be expected to reflect uteroplacental perfusion and as such may provide an investigative tool capable of assessing the dynamics of uteroplacental function in a variety of clinical conditions.

17-Ketosteroids↗

PubMed1975

[Study on metabolic pathway from dehydroepiandrosterone sulfate to estrogen in late pregnancy (author's transl)].

To investigate the metabolic pathway from dehydroepiandrosterone sulfate (DHAS) to estriol (E3) in late human pregnancy, DHAS (50 to 100 mg) was given intravenously or intraamniotically to 13 volunteers (from cases of normal pregnant women, pregnant women with a live anencephalic fetus, intrauterine fetal death or hydatidiform mole and a patient complicated with cancer of the cervix). Urinary estrogens, serum unconjugated estrogens and urinary dehydroepiandrosterone (DHA) and 16alpha-hydroxy-dehydroepiandrosterone (16alpha-OH-DHA) were measured before and after injection. Brown's method (1955) has been used to measure urinary three fractions of estrogens, estrone (E1), estradiol (E2) and estriol (E3). Serum unconjugated estrogens, estrone (SE1), estradiol (SE2) and estriol (SE3) were determined by a radioimmunoassay technique (a modification of the method of Makino, 1973). Urinary DHA and alpha-OH-DHA were separated by a modification of the method of Lakshmanan and Lieberman (1954) and by thin layer chromatography, and estimated by the method of Oertel and Eiknes (1959). Results obtained were as follows: (1) In seven cases of pregnancy with a live anencephalic fetus the excretion of urinary estriol was very low and the ratio of E3/E1+E2 was much less than that in normal pregnancy. (2) In five women with a live anencephalic fetus the effect of intravenously injected DHAS was studied. In each case there was a remarkable in urinary E3, E1 and E2, while no remarkable difference between the ratio of E3/E1+E2 before and after administration of DHAS was found. (3) DHAS was given intraamniotically to two women with a live anencephalic fetus. A greater rise of the ratio of E3/E1+E2 after administration of DHAS was found, compared to the control. (4) DHAS circulating in the maternal organism is converted to E3 largely via a phenolic pathway (DHAS-E1-E3), whereas DHAS circulating within the feto-placental compartment is converted to E3 via both phenolic and neutral intermediates (DHAS-16alpha-OH-DHAS-E3). (5) The ratio of urinary 16alpha-OH-DHA/DHA in pregnancy with a live anencephalic fetus was greater than that in non-pregnant woman. This suggests that 16alpha-hydroxylase activity in pregnancy is elevated. (6) Increases in serum unconjugated E1, E2 and E3 after intravenous administration of DHAS in three pregnant women with a live anencephalic fetus were found.

Adult↗

PubMed1978

Biosynthetic pathways for corticoids and androgen formation in human fetal adrenal tissue in vitro.

Eleven incubations of minced human fetal adrenal tissue from two fetuses at midtrimester of pregnancy terminated for socio-economic reasons, were performed for different periods of time with labelled pregnenolone, progesterone, 17alpha-hydroxyprogesterone and deoxycorticosterone (DOC). The order of magnitudes of enzyme activity when progesterone was used as a substrate and incubated with midterm fetal adrenals was 17alpha-hydroxylase, 21-hydroxylase and 16alpha-hydroxylase. The activity of 3beta-hydroxysteroid dehydrogenase and delta5-4 isomerase was almost negligible as compared to other enzymic activities as mentioned above. Similar biosynthetic pathways for adrenal corticoids formation were observed in human fetal adrenals as reported in human adults and animals; once progesterone was converted into DOC, further 17alpha-hydroxylation did not take place.

Adrenal Cortex Hormones↗

PubMed1978

In vitro effect of 16alpha-hydroxyprogesterone on the enzyme activities related to androgen production in human testes.

Progesterone was converted in vitro to 16alpha- and 17alpha-hydroxyprogesterones in the presence of NADPH by the testicular microsomal fraction (precipitate at 10 000 x g-105 000 x g) obtained from patients with prostatic carcinoma. 16alpha-Hydroxyprogesterone was not metabolized by either the microsomal or the cytosol fractions, and accumulated in the incubation medium. 16alpha-Hydroxyprogesterone competitively inhibited the activity of the C-17-C-20 lyase in the testicular microsomal fraction with an estimated inhibitor constant of 72 micron. Moreover, the 16alpha-hydroxyprogesterone non-competitively inhibited the activity of the 20alpha-hydroxysteroid dehydrogenase in the testicular cytosol fraction and had an estimated inhibitor constant of 52.9 micron. Other testicular enzymes related to steroid metabolism, such as delta5-3beta-hydroxysteroid dehydrogenase coupled with the delta4-delta5 isomerase, 16alpha-hydroxylase, 17alpha-hydroxylase, and 17beta-hydroxysteroid dehydrogenase were not influenced in vitro by 16alpha-hydroxyprogesterone at the concentration of 0.1 mM. From these findings, it is concluded that 16alpha-hydroxyprogesterone inhibit specifically the cleavage of the side-chain of 17alpha-hydroxypregnenes in the course of androgen formation from pregnenolone in vitro.

Androgens↗

PubMed2026

Identification of a Functional CYP2C8 Variant Allele that Alters Splicing, Reduces Protein Expression, and Increases Drug Exposure.

This study investigated genetic determinants of the pharmacokinetics of the CYP2C8 index drugs repaglinide and gemfibrozil, and their interaction in healthy participants. Sequencing data from a study with montelukast revealed a novel functional CYP2C8 allele (rs2071426, CYP2C8*19), predicted to create an intronic splice donor site. In human liver samples, CYP2C8*19 associated with transcript-specific changes in CYP2C8 mRNA expression, reduced CYP2C8 protein expression, and decreased enzyme activity. Consistently, participants with the CYP2C8*19/*19 genotype had 45% greater area under the plasma repaglinide concentration-time curve from time zero to infinity (AUC0-∞) than participants with CYP2C8*1/*1 (P = 1.6 × 10-4). Participants with CYP2C8*1/*3 had 26% smaller AUC0-∞ (P = 0.0033) and those with CYP2C8*1/*4 had 51% greater AUC0-∞ (P = 8.2 × 10-4). The fold increase in repaglinide AUC0-∞ caused by gemfibrozil was 36% (P = 1.3 × 10-4) smaller in CYP2C8*19/*19 participants than in CYP2C8*1/*1 participants. In a genome-wide association study (GWAS), SLCO1B1 c.521 T>C (rs4149056) associated with increased repaglinide AUC0-∞ (P = 4.5 × 10-15; n = 172) and SLCO1A2 variants associated with decreased AUC0-∞ (P < 10-8). In a GWAS of repaglinide after gemfibrozil pretreatment, SLCO1C1 variants associated with decreased AUC0-∞ (P < 1.6 × 10-8; n = 66). Participants with the poor function SLCO1B1 genotype showed a 32% smaller fold increase in repaglinide AUC0-∞ following gemfibrozil than participants with the normal function SLCO1B1 genotype (P = 0.0045). This study characterizes CYP2C8*19 as a novel decreased function allele and shows that CYP2C8 and SLCO1B1 genotypes affect the gemfibrozil-repaglinide interaction.

Humans↗