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Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Many drugs are involved casually in this condition: barbiturates, halogenated insecticides, steroids, alcohol, collidin, allylisopropylacetamide, theophyllin, griseofulvin, and others. In barbiturates, characteristic chemical groups are associated with the induction (Figure 10). The most potent porphyria-inducing steroids are 5β-steroids, 5β-androstane (Cl9), and 5β-pregnane (C21).301 The wide structural variety of chemicals which modify the hepatic formation of porphyrins suggests that either they act on different sites or that some nonspecific receptor provides a common site of action. Lead poisoning is also a condition resulting in porphyria. The action of lead is probably related to inhibition of ferrochelatase activity, which requires glutathione. The enzyme is inactivated by lead through binding to the sulfhydryl groups.
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
Though there is evidence of underlying changes in GABAA receptor function in PMDD, the question of what causes these phenomena remains. One plausible mechanism is that GABAA receptors may be regulated by endogenous modulators, such as the neuroactive metabolites of steroid hormones. Generally, steroid hormones, such as corticosterone and progesterone, exert their effects over a relatively long time by acting as transcription factors that regulate protein expression. These compounds can, however, also be further processed into neuroactive metabolites, which are known as neurosteroids since they have rapid actions at nerve cell membrane receptors and are synthesized in the brain.53 Neuroactive steroids include tetrahydrodeoxycorticosterone (THDOC), a derivative of corticosterone, and allopregnanolone and pregnanolone (3a-hydroxγ-5α-pregnane-20-one and 3a-hydroxγ-5β-pregnane-20-one, respectively), which are neuroactive metabolites of progesterone.
In vitro modulation of multidrug resistance by pregnane steroids and in vivo inhibition of tumour development by 7α-OBz-11α(R)-OTHP-5β-pregnanedione in K562/R7 and H295R cell xenografts
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Ghina Alameh, Agnès Emptoz-Bonneton, Marc Rolland de Ravel, Eva L. Matera, Elisabeth Mappus, Patrick Balaguer, Luc Rocheblave, Thierry Lomberget, Charles Dumontet, Marc Le Borgne, Michel Pugeat, Catherine Grenot, Claude Y. Cuilleron
In vivo experiments were performed on xenografts of K562/R7 or NCI-H295R cells introduced on SCID mice26. The maximum tolerated dose of doxorubicin (1.5 mg/kg) was limited by the extreme sensitivity of SCID mice to doxorubicin toxicity, owing to their deficit in cellular mechanisms of DNA repair27. The maximum dose of the 5β-pregnane modulator 4 (8 mg/kg) was imposed by its limit of solubility optimised by employing the lowest amount of benzyl alcohol (6%) able to maintain the steroid soluble in physiological serum without impairing mice survival. Non-xenografted SCID mice co-treated with these optimised doses of doxorubicin and steroid modulator could survive beyond 40 days, thus suggesting the absence of strong toxic side-effects of this treatment.