The use of medicinal plants globally continues to grow [15]. It is not only an issue in lower-income countries due to the lack of accessibility to the orthodox health care system but also in middle and high-income countries, its use is considered prestigious where the medical plant has been well researched and tested [4]. In America, about 30% will resort to the use of Saw palmetto for prostate and LUTS disorders [16]. In Austria and Germany, as many as 90% of men prefer phytotherapy for prostate disorders [17]. In Ghana and some African countries, the use of C. membranaceus for prostate disorders continues to grow [18]. Not only do people seek it's exclusive it but also in combination with orthodox medicine and other medicinal plants [19]. C. membranaceus has been shown to inhibit BPH-1 cell proliferation [8]. However, studies have not been undertaken to evaluate the effect of the plant extract on DMEs.
The construction of the BPH animal model was to provide answers to the pathological condition, rather than the use of a normal animal model. Data has demonstrated that C.membranaceus is specifically prostate targeting among the various organs [9]. The experimental design that was steroid-based included a model (the model group - III) that was not treated with the extract to demonstrate the direct effect of the BPH castration-steroid model on DMEs. Furthermore, to compare the effect of the extract as a medicinal plant as against the conventional drug, a finasteride control model was also included.
In light of this holistic experimental design, careful interpretation is given to the data. The effect of CYP3A4 on the various drug, drug-herb, drug-herb-herb administrations remained the same in all groups. Testosterone was administered to maintain the prostate enlarged throughout the experiment. However, the effect on this procedure did not show any disadvantage as the model group (group III) had levels that were as low as the Finasteride group (group IV) of which no difference existed between the two. There was therefore a significant lowing in all the groups compared to the control group. There was a 31-41x reduction in CYP3A4 in all groups compared to the control group. The metabolism of testosterone to DHT is CYP450 dependent [20].
Endogenous testosterone is metabolized by the body and is not an inhibitor of CYP450. The administration of testosterone in this model does appear to have affected CYP3A4. However, post hoc analysis demonstrated that the finasteride and the plant extract significantly inhibited the CYP3A4 (Table 6). CYP3A4 may be highly expressed under normal conditions but suppressed in disease states. For example, CYP450 3A5 is highly expressed in normal human prostate cells is much lower in the disease state [21].
Fifty-seven (57) plant extracts used in Traditional Chinese Medicine have been reported to inhibit CYP3A4 activity22 Similarly, PC-SPES a multiherbal preparation (8 plants) for prostate cancer has been shown to inhibit CYP3A4 expression and activity23. CYP3A4 inhibition seen in this study could, therefore, be due to both disease and medication although CT appears to have slightly less inhibitory effect compared to the others test groups (Table 2).
CYP2D6 activity was inhibited in the same manner as CYP3A4 with an inhibition of 38 to 46% (Table 11). The main function of CYP2D6 is metabolizing and eliminating as much as 25% of drugs of clinical use. Bush mint (Hyptis suaveolens) and spreading hogweed (Boerhavia diffusa) medicinal plant extracts differentially affect activities of CYP2D6; and the crude aqueous extracts inhibits DMEs CYP2D6 in a reversible and time-dependent manner [23].
Not only do medicinal plants inhibit CYP450, but some fruits and juices also have similar potentials [24]. Four (4) out 15 of traditional preparations and methanol extracts of medicinal plants from Papua New Guinea exhibited a similar Cytochrome P450 inhibitory effect on CYP2D6. Besides, drug interactions with Saw palmetto (Serenoa repens) have been reported. Saw palmetto has been shown to potently inhibit CYP2D6 in vitro [25]. However, a clinical study with Saw palmetto reported no significant effect on CYP1A2, CYP2D6, CYP2E1 or CYP3A4 activity during supplementation for 28 days [26, 27].
CYP1A2 was the only phase 1 DME that showed a different trend by increasing. CYP1A2 metabolizes various environmental procarcinogens, such as heterocyclic amines, nitrosamines, and aflatoxin B1 [28]. Cigarette smoke increases CYP1A2 activity in humans.29 Cruciferous vegetables and well-cooked meat also increase CYP1A2 activity however, certain drugs and diets have been associated with reduced CYP1A2 activity in vivo [29]. Extracts of Bowiea volubilis and Spirostachys Africana are known to have inhibitory activity on CYP1A2 when the crude aqueous extract is incubated with hepatic microsomes [30]. B. monnieri used for improving memory and anxiety reduced the catalytic activities of CYP3A4, CYP2C9, and CYP2C19 to less than 10% compared to the total activity [31]. Recent use of kratom (Mitragyna speciosa) a native herb of Southeast Asia as a recreational drug because of its psychoactive properties is of concern because a few reports available indicate that kratom affects CYP450 activities [32]. Others such as the aqueous and ethanol extract of Z. jujuba have been shown to increase CYP1A mediated conversion of phenacetin to acetaminophen [29].
Phyllanthus amarus a herb in Euphorbiaceae family is broadly considered as a hepatoprotective and hypoglycaemic agent by traditional practitioners as well as conventional researchers is known to considerably inhibit CYP1A2 and CYP2C9 across a range of concentrations [33–35].
CYP1A2 is important for the metabolism of endogenous substrates [36] and activation of many environmental carcinogens including dietary heterocyclic amines, certain mycotoxins, tobacco-specific nitrosamines, and aryl amines [28]. It has been suggested that sustained induction of CYP1A2 for example, maybe beneficial in women, as through 2-hydroxylation it increases estrogen clearance to anti-oestrogenic metabolites, so acting to protect against estrogen-driven tumors [37].
In this study, GSTM1 was significantly elevated in all groups apart from the model group. Hence, elevations will be purely due to the plant extract or in the case of group IV, finasteride. Induction of this enzyme was highest in group II. The basic function of the GSTM class of enzymes is in the detoxification of electrophilic compounds, including carcinogens, environmental toxins, and oxidative stress agents as well as therapeutic drugs, by conjugation with glutathione [37]. An induction in GSTM1 is useful as it will metabolize and conjugate carcinogens. GSH binding reduces the toxicity and increases the solubility of the toxic compound enhancing its excretion from the cell 37. Medicines or diet components that enhance GST expression may assist in cancer prevention because maintaining a high and constant level of GST attenuates the effects of carcinogenic compounds [38]. Conversely, when GSTM1 hydrolyzes cancer chemotherapeutics or activates the anti-apoptosis pathway cancer drug resistance is induced through activation of autophagy [38].