Identification of Three Human POLH Germline Variants Defective in Complementing the UV- and Cisplatin-Sensitivity of POLH-Deficient Cells.

DNA polymerase (pol) η is responsible for error-free translesion DNA synthesis (TLS) opposite ultraviolet light (UV)-induced - cyclobutane thymine dimers (CTDs) and cisplatin-induced intrastrand guanine crosslinks. POLH deficiency causes one form of the skin cancer-prone disease xeroderma pigmentosum variant (XPV) and cisplatin sensitivity, but the functional impacts of its germline variants remain unclear. We evaluated the functional properties of eight human POLH germline in silico-predicted deleterious missense variants, using biochemical and cell-based assays.

Metabolism and Interactions of Chloroquine and Hydroxychloroquine with Human Cytochrome P450 Enzymes and Drug Transporters.

Background: In clinical practice, chloroquine and hydroxychloroquine are often co-administered with other drugs in the treatment of malaria, chronic inflammatory diseases, and COVID-19. Therefore, their metabolic properties and the effects on the activity of cytochrome P450 (P450, CYP) enzymes and drug transporters should be considered when developing the most efficient treatments for patients.

Methods: Scientific literature on the interactions of chloroquine and hydroxychloroquine with human P450 enzymes and drug transporters, was searched using PUBMED.

7-ketocholesterol and 27-hydroxycholesterol decreased doxorubicin sensitivity in breast cancer cells: estrogenic activity and mTOR pathway.

Hypercholesterolemia is one of the risk factors for poor outcome in breast cancer therapy. To elucidate the influence of the main circulating oxysterols, cholesterol oxidation products, on the cell-killing effect of doxorubicin, cells were exposed to oxysterols at a subtoxic concentration. When cells were exposed to oxysterols in fetal bovine serum-supplemented medium, 7-ketocholesterol (7-KC), but not 27-hydroxycholesterol (27-HC), decreased the cytotoxicity of doxorubicin in MCF-7 (high estrogen receptor (ER)α/ERβ ratio) cells and the decreased cytotoxicity was restored by the P-glycoprotein inhibitor verapamil.

Selective changes in cholesterol metabolite levels in plasma of breast cancer patients after tumor removal.

Introduction: Oxygenated metabolites of cholesterol (“oxysterols”) can influence carcinogenesis and contribute to resistance to endocrine therapy, an effect mostly described .

Objectives: We sought to establish a method for screening plasma levels of oxysterols in breast cancer patients, estimate their individual variability and detection limits, and provide basic information about their roles in tumor biology.

Method: Liquid-chromatography coupled with tandem mass spectrometry was used for determination of levels of 25-hydroxycholesterol, 27-hydroxycholesterol, 7-hydroxycholesterol, and 7-ketocholesterol in plasma sample pairs from patients before and 12–24 months after surgical removal of tumors (n=24).

Human cytochrome P450 27C1 catalyzes 3,4-desaturation of retinoids.

In humans, a considerable fraction of the retinoid pool in skin is derived from vitamin A2 (all-trans 3,4-dehydroretinal). Vitamin A2 may be locally generated by keratinocytes, which can convert vitamin A1 (all-trans retinol) into vitamin A2 in cell culture. We report that human cytochrome P450 (hP450) 27C1, a previously 'orphan' enzyme, can catalyze this reaction.