The increase in urinary excretion of 6 beta‐hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction.

Ged, Cécile; Rouillon, J. M.; Pichard, Lydiane; Combalbert, Jean; Bressot, N; Bories, P; Michel, H.; Beaune, Philippe; Maurel, Patrick

doi:10.1111/j.1365-2125.1989.tb03516.x

Cited by 310 publications

(170 citation statements)

References 63 publications

(89 reference statements)

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“…The effects on quinidine metabolism found in this study are readily explainable by a rifampicin mediated induction of hepatic CYP3A4. Cortisol metabolic ratio increased 5 times in this study, strongly indicating an induction of hepatic CYP3A4 (Ged et al 1989). The magnitude of the effects in this study are similar to those found by Twum-Barima & Carruthers (1 98 1).…”

Section: Discussionsupporting

confidence: 80%

“…Cortisol and 6-P-hydroxycortisol were analysed by HPLC (Lykkesfeldt et al 1994) and the metabolic ratio was calculated according to Ged et al (1989) as:…”

Section: Mephenytoinmentioning

confidence: 99%

“…Rifampicin, a rifamycin derivative, is a clinically widely used antibiotic, which is especially effective in combination therapy against tuberculosis. Rifampicin is an inducer of several enzymes in the human cytochrome P450 system (Zilly et al 1975;Eichelbaum et al 1986;Ged et al 1989;Wietholtz et al 1995;Feng et al 1998), but the CYP3A4 enzyme seems especially susceptible to induction by rifampicin (Ged et a/. 1989;Watkins et a/.…”

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confidence: 99%

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1999

Pharmacology & Toxicology

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Abstract:We investigated the effect of cytochrome P450 induction by rifampicin on the in vivo oxidative metabolism of quinidine. The pharmacokinetics of a 200 mg oral single dose quinidine were studied before and after one week of daily treatment with 600 mg rifampicin in six healthy young male volunteers. Biomarker reactions of cytochrome P450 isozyme activities in the form of caffeine, sparteine, mephenytoin, tolbutamide and cortisol metabolism were applied. The median total apparent oral clearance and partial clearance by 3-hydroxylation of quinidine increased 9 times. The partial clearance by N-oxidation increased 6 times. The C,, and the elimination half life were reduced 3 times. No statistically significant changes were found for quinidine t , , , and renal clearance. The cortisol metabolic ratio increased 5 times, while no statistically significant effects were seen for other CYP marker reactions. The results indicate that the inductive effect of rifampicin is likely to be of clinical relevance particulary when used concomitantly with drugs metabolized by CYP3A4.Cytochome P4503A4 (CYP3A4) accounts for approximately 30% of the total human liver cytochrome content and contributes to the oxidative metabolism of a wide range of drugs. The activity of CYP3A4 varies at least 10 times among individuals (Shimada et al. 1994), and the search for a suitable biomarker reaction of CYP3A4 activity, in order to assess CYP3A4 activity on an individual basis, is intense.

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Section: Discussionsupporting

confidence: 80%

“…Cortisol and 6-P-hydroxycortisol were analysed by HPLC (Lykkesfeldt et al 1994) and the metabolic ratio was calculated according to Ged et al (1989) as:…”

Section: Mephenytoinmentioning

confidence: 99%

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confidence: 99%

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1999

Pharmacology & Toxicology

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“…It is also the case that both endogenous cortisol and alprazolam are substrates for cytochrome P450-3A4 (CYP3A4), which is responsible for metabolism to 6b-hydroxycortisol and 4-and a-hydroxyalprazolam (Ged et al, 1989;von Moltke et al, 1994). There is evidence that CYP3A4 can accommodate more than one substance and that interactions with a particular substrate can impact on the metabolism of the other (Wang et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Interdose Elevation in Plasma Cortisol During Chronic Treatment with Alprazolam but not Lorazepam in the Elderly

Pomara

Willoughby

Ritchie

et al. 2003

Neuropsychopharmacol

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Benzodiazepines (BZPs) have been shown to reduce hypothalamic-pituitary-adrenal (HPA) axis activity acutely in normal humans. In contrast, the effects of chronic BZP treatment on the HPA axis have not been well studied, especially in the geriatric population. This study examined the acute and chronic effects (3 weeks) of alprazolam and lorazepam on plasma cortisol in 68 subjects (60-83 years) who received 0.25 or 0.50 mg b.i.d. alprazolam, or 0.50 or 1.0 mg b.i.d. lorazepam, or placebo orally according to a randomized, doubleblind, placebo-controlled parallel design. Memory assessment and blood samples for plasma cortisol were obtained prior to the morning dose on days 0, 7, 14, and 21, and at 1, 2.5, and 5 h postdrug on days 0 and 21. Assessments of anxiety and depression were carried out at days 0, 7, 14, and 21 before drug administration. Plasma cortisol was affected compared to placebo only by the 0.5 mg alprazolam dose. During the first and the last day of treatment, there was a significant drop in cortisol at 2.5 h after alprazolam compared to placebo. The predose cortisol levels increased significantly during chronic alprazolam treatment, and correlations were found between these cortisol changes and changes in depression, anxiety, and memory scores. These findings suggest that even a short period of chronic treatment with alprazolam, but not lorazepam, may result in interdose HPA axis activation in the elderly, consistent with drug withdrawal. If confirmed, this effect may contribute to an increased risk for drug escalation and dependence during chronic alprazolam treatment.

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“…1989). and cortisol (Ged et al, 1989). Screening of a bacteriophage Agtll expression cDNA library using antibodies raised against P450 N F led to the isolation oftwo clones designated NF25 (Beaune et al, 1986) and NFlO (Bork et al, 1989).…”

mentioning

confidence: 99%

Expression of human liver cytochrome P450 IIIA4 in yeast

Renaud

Cullin

Pompon

et al. 1990

European Journal of Biochemistry

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Cytochrome P-450 (P450) NF, a member of the P450 IIIA subfamily, is the major contributor to the oxidation of the calcium-channel blocker nifedipine in human liver microsomes. A cDNA clone designated NF25 encoding for human P450 NF was isolated from a bacteriophage (pVNF25) showed a ferrous -CO spectrum typical of cytochrome P-450. Microsomal preparations contained a protein with an apparent molecular mass identical to that of P450-5 (a form isolated from human liver indistinguishable from P450 NF) that was not present in microsomes from control yeast (transformed with pYeDP1/8-2 alone), as revealed by immunoblotting with anti-P450-5 antibodies. On the other hand, antibodies raised in rabbits against human liver P450 IIC8-10 and rat liver P450 IA1 and P450 IIEl did not recognize yeastexpressed P450 NF25. The P450 NF25 content in microsomes was about 90 pmol/mg protein. Microsomal, yeast-expressed P450 NF25 exhibited a high affinity for different substrates including macrolide antibiotics, dihydroergotamine and miconazole as shown by difference visible spectroscopy. Microsomal suspensions containing P450 NF25 were also able to catalyze several oxidation reactions that were expected from the activities of the protein isolated from human liver, including nifedipine 1 ,Coxidation, quinidine 3-hydroxylation and Noxygenation, and N-demethylation of the macrolide antibiotics erythromycin and troleandomycin. The yeast endogenous NADPH -cytochrome P-450 reductase thus couples efficiently with the heterologous P450 NF25 though its level is far lower than that of its ortholog in human liver. Indeed addition of rabbit liver NADPHcytochrome P-450 reductase increased the oxidation rates. Rabbit liver cytochrome b5 also caused a marked enhancement of catalytic activities, as had been noted previously for this particular P450 enzyme in a reconstituted system involving the protein purified from human liver. Furthermore, the level of the yeast endogenous cytochrome P-450 (lanosterol 14-demethylase) has been found to be negligible compared to the heterologously expressed cytochrome P-450 (30 times less). Thus, yeast microsomes containing P450 NF25 constitute by themselves a good functional model for studying the binding capacities and catalytic activities of this individual form of human hepatic cytochrome P-450.Cytochromes P-450 (P450s) are members of a superfamily of heme proteins that catalyze the oxidation of a wide variety of endogenous and exogenous compounds including most drugs and carcinogens, the existence of multiple enzymes being the origin of the broad substrate specificity (Gonzalez, 1989). This enzyme multiplicity is now well established on the basis of purification, amino acid composition, electrophoretic and

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The increase in urinary excretion of 6 beta‐hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction.

Cited by 310 publications

References 63 publications

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Interdose Elevation in Plasma Cortisol During Chronic Treatment with Alprazolam but not Lorazepam in the Elderly

Expression of human liver cytochrome P450 IIIA4 in yeast

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