Genistein (GNT) (IUPAC: 5,7-dihydroxy-3-(4-hydroxyphenyl)chromen-4-one) is a phytoestrogen isoflavone that is widely available in soybean, mature seeds, and raw soy-related food (5.6–276 mg/100 g)
[1] and legumes (0.2–0.6 mg/100 g)
[2]. It possesses lower oral bioavailability, perhaps due to its high solubility in several polar solvents such as acetone, dimethylsulfoxide, and ethanol, and its poor solubility in water
[3]. The oral administration of GNT results in high absorption with a t
max (transport maximum) of 5–6 h and t1/2 of 8 h
[4][5]. GNT is rapidly distributed throughout the body by crossing the placental and blood–brain barriers. GNT is most abundant in the gastrointestinal tract and liver tissue distribution, consistent with its enterohepatic recycling
[6]. GNT is absorbed rapidly and nearly completely in vivo. It showed high permeability in Caco-2 (3 × 10
−5 cm/s) and Madin–Darby canine kidney (MDCKII) cells, where passive diffusion is the major transport mechanism, but breast cancer resistance protein (BCRP) may play a role in limiting its intestinal absorption
[7][8][9]. In vivo, GNT undergoes a complex and extensive metabolic process that includes oxidation, reduction, conjugation, glucuronidation, sulfation, and limited CYP reaction
[10][11][12][13][14][15]. Coldham et al. found that GNT has the highest concentrations in the gut (18.5 μg/g), followed by the liver (0.98 μg/g), plasma (0.79 μg/g), and reproductive tissues (uterus, ovary, vagina, and prostate, ranging from 0.12 to 0.28 μg/g) in rats
[16]. The excretion of GNT depends on the activity of conjugating enzymes and relies on the efflux transporters’ capacity
[17]. In vivo, ADME studies revealed that GNT metabolites are excreted via the intestinal, biliary, and renal tracts
[18][19]. Although there is limited evidence that consuming large amounts of GNT in the diet causes a deleterious effect in humans, the toxicity of GNT on fertility and fetal development has been extensively studied in recent years. Several studies have demonstrated that therapeutically relevant doses of GNT have a harmful effect on BC differentiation, the estrous cycle, and fertility in rodent models
[20][21]. This natural phytochemical can exhibit a wide range of important therapeutic activities, including antioxidant
[22], anti-inflammatory
[23], antibacterial
[24], antiviral
[25], antidiabetic
[26], and anticancer activities
[27]. GNT has proven its ability against various types of human cancers such as lung
[28], liver
[29], prostate
[30], pancreatic
[31], skin
[32], cervical
[33], uterine
[34], colon
[35], kidney
[36], bladder
[37], neuroblastoma
[38], gastric
[39], esophageal
[40], pituitary
[41], salivary gland
[42], testicular
[43], ovarian
[44], and finally, breast cancer
[45].