Organophosphorus chemicals: potent inhibitors of the human metabolism of steroid hormones and xenobiotics

Although it has been known for some time that organophosphate chemicals containing the P = S moiety are irreversible inhibitors of cytochrome P450, this knowledge has not been generally applied to the human metabolism of xenobiotics. Recent studies have demonstrated that organophosphate insecticides containing this moiety are potent inhibitors of the metabolism of both xenobiotics and endogenous substrates by human liver microsomes and by specific human cytochrome P450 isoforms.     

Identification of steroid drugs by13C NMR spectroscopy,androgenic and anabolic hormones

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 26, No. 5, pp. 86–88, May, 1992.     

Effects of steroid hormones in vitro on adrenal xenobiotic metabolism in the guinea pig

Studies were carried out to determine the effects of steroid hormones in vitro on adrenal and hepatic microsomal benzphetamine demethylation and benzo[a] pyrene hydroxylation. Testosterone inhibited adrenal drug metabolism but had no effect on hepatic enzymes, whereas 6β-hydroxytestosterone had no effect in either tissue. All of the corticosteroids tested (cortisol, corticosterone, 11-deoxycortisol, 11-deoxycorticosterone, progesterone, and 17-hydroxyprogesterone) produced a concentration-dependent inhibition of adrenal drug metabolism, but had little or no effect on hepatic metabolism. The 17-deoxy-steroids were more potent inhibitors of adrenal metabolism than were their 17-hydroxylated counterparts. Cortisol was a potent inhibitor of adrenal benzphetamine and benzo[a]pyrene metabolism, produced a type I difference spectrum in adrenal microsomes, and diminished the magnitude of the benzphetamine-induced spectrum; 6 β-hydroxycortisol had none of these effects. Prior addition of benzphetamine to adrenal microsomes reduced the size of cortisol-induced spectral change. The results demonstrate that the effects of corticosteroids in vitro are relatively specific for adrenal enzymes and established a close association between the 6 β-hydroxylase and some drug-metabolizing enzymes. Adrenal steroids may have an important role in the regulation of adrenal xenobiotic metabolism.     

Rotenone-induced PC12 cell toxicity is caused by oxidative stress resulting from altered dopamine metabolism.

Rotenone is a widely used pesticide. Administration of rotenone can induce biochemical and histological alterations similar to those of Parkinson's disease in rats, leading to the selective loss of dopaminergic neurons in the substantia nigra pars compacta. However, it remains unclear why rotenone seems to affect preferentially dopaminergic cells. To address this question, we studied the effects of rotenone on dopamine distribution and metabolism to determine the role of endogenous dopamine in rotenone-induced PC12 cells toxicity. Results showed that cell viability was decreased and intracellular dopamine concentration was increased with rotenone administration in a dose-dependent manner. Rotenone exposure led to changes of proteins and enzymes associated with dopamine synthesis and transportation in PC12 cells. Tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT(2)) were markedly down-regulated, and dopamine transporter (DAT) was up-regulated in the cells. The activity of monoamine oxidase (MAO) was also increased. In addition, rotenone increased ROS formation, which was clearly inhibited by the pretreatment of GSH. Similar inhibitions of ROS formation were also observed in PC12 cells pretreated with the classical dopamine transporter inhibitor of GBR-12909 and the MAO inhibitor l-deprenyl. Moreover, opposite effects were observed in PC12 cells pretreated with the specific VMAT(2) inhibitor reserpine. These results suggest that rotenone administration may interfere with dopamine distribution and metabolism, leading to dopamine accumulated in the cytoplasm of PC12 cells, which may contribute to the ROS formation and cell death. Therefore, the endogenous dopamine resulted from the altered dopamine metabolism and redistribution may play an important role in rotenone toxicity in dopamine neurons.     

Predisposition to uterine microbial contamination in the guinea-pig following administration of mucolytic drugs and steroid hormones.

Using guinea-pigs as a mammalian model, the effects of bromhexine hydrochloride, ethinyloestradiol, norethisterone acetate and prednisolone acetate on uterine microbial status were determined. Those drugs known to decrease mucus viscoelasticity predisposed to the entry of vaginal bacteria into the uterus, probably due to reduction of the cervical mucus barrier. Norethisterone acetate, which increases cervical mucus viscoelasticity, reduced these effects. The effects produced by the steroid hormones were independent of their immunosuppressive effects. The results also suggest that prednisolone acetate may exert oestrogen-like actions on cervical mucus.     

Effects of the antifungal agents on oxidative drug metabolism: clinical relevance

This article reviews the metabolic pharmacokinetic drug-drug interactions with the systemic antifungal agents: the azoles ketoconazole, miconazole, itraconazole and fluconazole, the allylamine terbinafine and the sulfonamide sulfamethoxazole. The majority of these interactions are metabolic and are caused by inhibition of cytochrome P450 (CYP)-mediated hepatic and/or small intestinal metabolism of coadministered drugs. Human liver microsomal studies in vitro, clinical case reports and controlled pharmacokinetic interaction studies in patients or healthy volunteers are reviewed. A brief overview of the CYP system and the contrasting effects of the antifungal agents on the different human drug-metabolising CYP isoforms is followed by discussion of the role of P-glycoprotein in presystemic extraction and the modulation of its function by the antifungal agents. Methods used for in vitro drug interaction studies and in vitro-in vivo scaling are then discussed, with specific emphasis on the azole antifungals. Ketoconazole and itraconazole are potent inhibitors of the major drug-metabolising CYP isoform in humans, CYP3A4. Coadministration of these drugs with CYP3A substrates such as cyclosporin, tacrolimus, alprazolam, triazolam, midazolam, nifedipine, felodipine, simvastatin, lovastatin, vincristine, terfenadine or astemizole can result in clinically significant drug interactions, some of which can be life-threatening. The interactions of ketoconazole with cyclosporin and tacrolimus have been applied for therapeutic purposes to allow a lower dosage and cost of the immunosuppressant and a reduced risk of fungal infections. The potency of fluconazole as a CYP3A4 inhibitor is much lower. Thus, clinical interactions of CYP3A substrates with this azole derivative are of lesser magnitude, and are generally observed only with fluconazole dosages of > or =200 mg/day. Fluconazole, miconazole and sulfamethoxazole are potent inhibitors of CYP2C9. Coadministration of phenytoin, warfarin, sulfamethoxazole and losartan with fluconazole results in clinically significant drug interactions. Fluconazole is a potent inhibitor of CYP2C19 in vitro, although the clinical significance of this has not been investigated. No clinically significant drug interactions have been predicted or documented between the azoles and drugs that are primarily metabolised by CYP1A2, 2D6 or 2E1. Terbinafine is a potent inhibitor of CYP2D6 and may cause clinically significant interactions with coadministered substrates of this isoform, such as nortriptyline, desipramine, perphenazine, metoprolol, encainide and propafenone. On the basis of the existing in vitro and in vivo data, drug interactions of terbinafine with substrates of other CYP isoforms are unlikely.     

Biosynthesis, metabolism and regulation of steroid hormones secretion in the placental phase of gestation in the rat

The regulation of biosynthesis of steroid hormones in the pre-placental stage and in placental phase of pregnancy in the rat is described. On the ground of our own studies a concept of an ovarian-placental unit in the rat has been formulated. This unit is characterized by coupled biosynthesis and secretion of steroid hormones in the placental stage of rat pregnancy.     

药物致光敏感性和光毒性反应

引起皮肤反应的物质很多,但很多情况难于弄清何种物质(药物)所致。其中光敏性和光毒性引起的皮肤反应．占有不小的比例。认识光敏性和光毒性药物所致皮肤、粘膜和眼部的不良反应,对诊断和治疗无疑是有价值的。笔者收集药物致光敏感不良反应的资料,以期达到此目的。     

A comparative study of the effect of some steroid hormones on the response of rats to other drugs.

The effect of a series of steroid hormones on the pentetrazol convulsing action, hexobarbital narcotic action and hepatic drug metabolizing enzyme activities was determined in rats. All steroid compounds used antagonized the pentetrazol effect: the most potent was cortisone and the least potent testosterone. Glucocorticoids and androgens shortened the hexobarbital sleeping time and increased the hepatic drug metabolizing enzyme activity. Estradiol exhibited the opposite effect, whereas progesterone and desoxycorticosterone did not affect these two parameters.     

The interaction of oral hypoglycaemic drugs with insulin on steroid metabolism in hepatocytes isolated from control and diabetic male rats

The effects of the oral hypoglycaemic drugs, phenformin and tolbutamide, and insulin, alone and in combination, on steroid metabolism in hepatocytes isolated from control and streptozotocin-diabetic male rats has been studied. Both phenformin and tolbutamide mimic the action of insulin in stimulating hepatic steroid metabolism in a dose-dependent manner in control cells. Unlike insulin, however, both drugs give a similar effect in cells derived from diabetic animals although to a lesser extent. Both drugs can partially restore the effect of insulin in cells derived from diabetic animals. Biguanides and sulphonylureas, therefore, have a direct effect on liver cells to mimic insulin action and can still have an effect under conditions where insulin is inactive. Both types of oral hypoglycaemics can also affect insulin-insensitive cells isolated from diabetic rat liver to restore to a certain extent their response to insulin.