CYTOCHROME P450, ESTROGEN METABOLITES AND SUPEROXIDE RADICALS IN BREAST CANCER INITIATION AND PROGRESSION

Burlaka A.P.¹, Motuzyuk I.M.², Sydorchuk O.I.², Virko S.V.³

• ¹R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv, Ukraine
• ²O.O. Bogomolets National Medical University
• ³V.E. Lashkaryov Institute of Semiconductor Physics, NAS of Ukraine, Kyiv, Ukraine

Aim: to investigate levels of cytochrome P450 and its CYP 1A2, CYP 1B1 isoforms in tumor tissue (TT) and mammary adipose tissue (MAT) in patients with breast cancer (BC). Object and methods: Twenty eight patients with stage II (T₃N₀M₀) triple-negative molecular subtype BC were involved in the study. Fifteen patients had normal body mass (BMI < 25 kg/m²), 13 — were overweight (BMI ≥ 25 kg/m²). Twenty eight samples of TT, 25 of MAT taken at a distance of 3 cm from the tumor node and 27 of MAT on the tumor border were investigated. The levels of oxidized, low-spin and high-spin cytochrome P450 and its CYP 1A2 and CYP 1B1 isoforms were examined by electron paramagnetic resonance and spectrophotometrically. Results: it was shown that the levels of cytochrome Р450 CYP 1А2 in TT and MAT bordering with the tumor tissue were lower than that of Р450 CYP 1B1 independently of patients’ BMI. In MAT taken 3 cm from the tumor nodule distribution of P450 isoforms was the opposite. Three cm apart from the tumor nodule, semiquinone levels were 0.48 ± 0.02 relative units, while in MAT bordering the tumor tissue it increased to 0.89 ± 0.05 relative units (p < 0.05). TT is characterized by the highest levels of estrogen’s free radical metabolites (2.23 ± 0.09 relative units). Quinones and theirs anion-radicals, semiquinones, are a class of toxic estrogen’s intermediates that can induce a number of adverse effects. The mechanism of quinones’ toxic effect is complex. Obviously, the direct oxidation of SH groups in mitochondrial FeS-containing proteins and the production of superoxide radicals are the main processes. Conclusion: in patients with BC, there was revealed the increase in oxidative metabolism of estrogen due to elevated levels of CYP 1B1 and decreased activity of CYP 1A2 in cells of TT and MAT bordering the tumor tissue. Unregulated growth of estrogen’s metabolite levels causes mitochondria’s metabolism reprogramming in MAT cells, increased generation of superoxide radicals, cellular hypoxia and instability of the genome functioning. Regulation of cytochrome P450 activity is a critical mechanism in estrogen homeostasis in the prevention of BC and monitoring of the tumor process.