Fagron North America, IACP, NCPA: Nominators Pharmacy Compounding Advisory Committee review of Chrysin June 23, 2016 Chrysin • Naturally occurring bioflavonoid and polyphenolic compound • Found in passion flower indian trumpet flower, honeycomb, chamomile and oyster mushrooms Chrysin • Bioflavonoids such as chrysin can act as chemical messengers • Necessary in the production of plant pigmentations • Involved in UV filtration • Influence the symbiotic relationships of nitrogen fixation Chrysin • FDA has stated that it is a small molecule, can be characterized easily, and is relatively stable under ordinary storage conditions • Chrysin actually has a molecular size of 254.2375 g/mol • Molecular weight consistent with that of steroid hormones Oral supplement dosing • Because of low bioavailability oral dosing is typically referenced at 400 mg – 3 g Br J Clin Pharmacol. 2001 Feb; 51(2): 143–146. Disposition and metabolism of the flavonoid chrysin in normal volunteers T Walle, Y Otake, J A Brubaker, U K Walle, and P V Halushka Conculsion Even though the systemic availability of chrysin appears to be low, this does not exclude the occurrence of local biological effects of the flavonoid, particularly in the intestine. In summary, this study supports the view that the bioavailability of chrysin, and possibly other flavonoids, in humans is very low, due to extensive presystemic intestinal as well as hepatic glucuronidation… Topical administration feasibility • It has been shown in the study of trans dermal drug delivery systems that one of the main criteria for feasibility of drug delivery through the skin is small molecular size of 500 Daltons or less • Other references states that unionized entities have better absorption. chrysin is non polar. ABSTRACT Transdermal drug delivery is the application of drug on the skin surface so that it can permeate through the skin and reaches the systemic circulation. Skin contains 10-70 hair follicles and 200-250 sweat ducts per cm2 of the skin so it is easily accessible by drugs and provides a mean of drug delivery via the skin. It was recognized as drug delivery route several decades ago but stratum corneum of the skin poses a problem in permeation of drugs. Transdermal route have a number of advantages over conventional drug delivery routes such as avoidance of first pass effect, enhanced bioavailability, patient compliance, steady state plasma drug level, painless delivery of drugs, ease of application and easy removal of patch in case of toxicity… Jhawat VC, Saini V, Kamboj S, Maggon N. Transdermal Drug Delivery Systems : Approaches and Advancements in Drug Absorption through Skin. 2013;20(1):47-56. Chrysin efficacy potential Environ Health Perspect. 1998 Feb;106(2):85-92. Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study. Kao YC1, Zhou C, Sherman M, Laughton CA, Chen S. Abstract Flavone and isoflavone phytoestrogens are plant chemicals and are known to be competitive inhibitors of cytochrome P450 aromatase with respect to the androgen substrate. Aromatase is the enzyme that converts androgen to estrogen; therefore, these plant chemicals are thought to be capable of modifying the estrogen level in women. In this study, the inhibition profiles of four flavones [chrysin (5, 7- dihydroxyflavone), 7,8-dihydroxyflavone, baicalein (5,6,7-trihydroxyflavone), and galangin (3,5,7-trihydroxyflavone)], two isoflavones [genistein (4,5,7- trihydroxyisoflavone) and biochanin A (5,7-dihydroxy-4-methoxyisoflavone)], one flavanone [naringenin (4, 5,7-trihydroxyflavanone)], and one naphthoflavone (alpha-naphthoflavone) on the wild-type and six human aromatase mutants (I133Y, P308F, D309A, T310S, I395F, and I474Y) were determined. In combination with computer modeling, the binding characteristics and the structure requirement for flavone and isoflavone phytoestrogens to inhibit human aromatase were obtained. These compounds were found to bind to the active site of aromatase in an orientation in which rings A and C mimic rings D and C of the androgen substrate, respectively. This study also provides a molecular basis as to why isoflavones are significantly poorer inhibitors of aromatase than flavones. Chrysin efficacy potential J Endocrinol. 2008 May;197(2):315-23. doi: 10.1677/JOE-07-0282. Chrysin, a natural flavonoid enhances steroidogenesis and steroidogenic acute regulatory protein gene expression in mouse Leydig cells. Jana K1, Yin X, Schiffer RB, Chen JJ, Pandey AK, Stocco DM, Grammas P, Wang X. Abstract During the aging process of males, testosterone biosynthesis declines in testicular Leydig cells resulting in decreases in various physiological functions. To explore the possibility of delaying the decline using food supplements, we have studied steroidogenic effects of a natural flavonoid, chrysin, in mouse Leydig cells. Chrysin dramatically increased cyclic AMP (cAMP)-induced steroidogenesis in MA-10 mouse Leydig tumor cells. This result was confirmed using Leydig cells isolated from mouse testes. The steroidogenic effect of chrysin is not associated with an increase in expression of the P450 side-chain cleavage enzyme, required for the conversion of cholesterol to pregnenolone. In addition, when 22(R)hydroxylcholesterol was used as a substrate, chrysin induced a non-significant increase in steroid hormone, suggesting that the majority of the observed increase in steroidogenesis was due to the increased supply of substrate cholesterol. These observations were corroborated by showing that chrysin induced a marked increase in the expression of steroidogenic acute regulatory (StAR) protein, the factor that controls mitochondrial cholesterol transfer. Also, chrysin significantly increased StAR promoter activity and StAR mRNA level. Further studies indicated that this compound depressed expression of DAX-1, a repressor in StAR gene transcription. In the absence of cAMP, chrysin did not increase steroidogenesis. However, when a sub-threshold level of cAMP was used, StAR protein and steroid hormone were increased by chrysin to the levels seen with maximal stimulation of cAMP. These results suggest that while chrysin itself is unable to induce StAR gene expression and steroidogenesis, it appears to function by increasing the sensitivity of Leydig cells to cAMP stimulation. Chrysin efficacy potential J Med Food. 2002 Spring;5(1):43-8. Beneficial effects of chrysin and benzoflavone on virility in 2-year-old male rats. Dhawan K1, Kumar S, Sharma A. Abstract This work describes the potential usefulness of bioflavonoids for countering the deleterious effects of aging on male sexuality in 2-year-old rats. A flavone chrysin from Passiflora caerulea Linn. and a benzoflavone moiety (BZF) recently isolated from Passiflora incarnata Linn. were administered to 2-year-old male rats for a period of 30 days. After cessation of these treatments, there was a significant improvement in overall sexual functions in the rats given bioflavonoids, compared with control rats. The rats receiving chrysin (1 mg/kg) and BZF (10 mg/kg) exhibited increased libido when they were allowed to interact with nonestrous female rats. Additionally, both treated groups had increased sperm count, greater fertilization potential, and greater litter size when they were allowed to interact with proven proestrous female rats of a similar strain. BZF was more potent than chrysin as an antiaromatase agent and exhibited better effects on the sexual system of the 2- year-old male rats. Plant flavonoids have great potential for clinical and therapeutic applications against the physiological and biochemical effects of aging. Chrysin efficacy potential Andrologia. 2012 Jun;44(3):181-6. doi: 10.1111/j.1439-0272.2010.01127.x. Epub 2011 Mar 7. Beneficial effects of chrysin on the reproductive system of adult male rats. Ciftci O1, Ozdemir I, Aydin M, Beytur A. Abstract In this study, the beneficial effect of chrysin, a natural flavonoid currently under investigation due to its important biological activities, on reproductive system of rats was investigated. Rats (n = 16) were divided randomly into two equal groups. Rats in control group were given corn oil as carrier. Chrysin was orally administered at the dose of 50 mg kg(-1) per day by gavages, and it was dissolved in corn oil for 60 days. Tissue thiobarbituric acid reactive substances (TBARS) and glutathione (GSH) levels, antioxidant enzyme activity (CAT, SOD and GSH-Px), sperm parameters (motility, concentration and abnormal sperm rate), reproductive organ weight (testes, epididymis, vesicula seminalis, prostate) and serum testosterone levels were determined in the rats. Our results indicated that chrysin significantly increased GSH, CAT, GSH-Px and CuZn-SOD levels, but did not change the formation of TBARS significantly. In addition, sperm motility, sperm concentration and serum testosterone levels significantly increased, whereas abnormal sperm rate significantly decreased with chrysin treatment. In conclusion, it is suggested that treatment with chrysin can positively affect the reproductive system in rats, and it can be used for the treatment of male infertility. Mutagenicity • FDA points to study in bacteria strains using the Ames test. • Within the study below referenced chrysin showed Negative mutagenicty across every strain tested. • The Ames test has been shown to have greater sensitivity, specificity, and predictability over other forms of mutagenic testing in various carcinogen testing. D. Kirkland,