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Khellinoflavanone, a Semisynthetic Derivative of Khellin, Overcomes Benzo[a]pyrene Toxicity in Human Normal and Cancer Cells That Express CYP1A1.

ABSTRACT: Cytochrome P450 family 1 (CYP1) enzymes catalyze the metabolic activation of environmental procarcinogens such as benzo[a]pyrene, B[a]P, into carcinogens, which initiates the process of carcinogenesis. Thus, stopping the metabolic activation of procarcinogens can possibly prevent the onset of cancer. Several natural products have been reported to show unique ability in inhibiting CYP1 enzymes. We found that khellin, a naturally occurring furanochromone from Ammi visnaga, inhibits CYP1A1 enzyme with an IC50 value of 4.02 ?M in CYP1A1-overexpressing human HEK293 suspension cells. To further explore this natural product for discovery of more potent and selective CYP1A1 inhibitors, two sets of semisynthetic derivatives were prepared. Treatment of khellin with alkali results in opening of a pyrone ring, yielding khellinone (2). Claisen-Schmidt condensation of khellinone (2) with various aldehydes in presence of potassium hydroxide, at room temperature, provides a series of furanochalcones 3a-v (khellinochalcones). Treatment of khellinone (2) with aryl aldehydes in the presence of piperidine, under reflux, affords the flavanone series of compounds 4a-p (khellinoflavanones). The khellinoflavanone 4l potently inhibited CYP1A1 with an IC50 value of 140 nM in live cells, with 170-fold selectivity over CYP1B1 (IC50 for CYP1B1 = 23.8 ?M). Compound 4l at 3× IC50 concentration for inhibition of CYP1A1 completely protected HEK293 cells from CYP1A1-mediated B[a]P toxicity. Lung cancer cells, A549 (p53+) and Calu-1 (p53-null), blocked in growth at the S-phase by B[a]P were restored into the cell cycle by compound 4l. The results presented herein strongly indicate the potential of these khellin derivatives for further development as cancer chemopreventive agents.

SUBMITTER: Sharma R

PROVIDER: S-EPMC6645225 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Khellinoflavanone, a Semisynthetic Derivative of Khellin, Overcomes Benzo[a]pyrene Toxicity in Human Normal and Cancer Cells That Express CYP1A1.

Sharma Rajni R Williams Ibidapo S IS Gatchie Linda L Sonawane Vinay R VR Chaudhuri Bhabatosh B Bharate Sandip B SB

ACS omega 20180801 8

Cytochrome P450 family 1 (CYP1) enzymes catalyze the metabolic activation of environmental procarcinogens such as benzo[a]pyrene, B[a]P, into carcinogens, which initiates the process of carcinogenesis. Thus, stopping the metabolic activation of procarcinogens can possibly prevent the onset of cancer. Several natural products have been reported to show unique ability in inhibiting CYP1 enzymes. We found that khellin, a naturally occurring furanochromone from Ammi visnaga, inh ...[more]

PMID: 31458985

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Project description:The polycyclic aromatic hydrocarbon (PAH) benzo(a)pyrene (BP) is thought to bind covalently to DNA, through metabolism by cytochrome P450 1A1 (CYP1A1) and CYP1B1, and other enzymes, to form r7, t8, t9-trihydroxy-c-10-(N(2)-deoxyguanosyl)-7,8,9,10-tetrahydro-benzo[a]-pyrene (BPdG). Evaluation of RNA expression data, to understand the contribution of different metabolic enzymes to BPdG formation, is typically presented as fold-change observed upon BP exposure, leaving the actual number of RNA transcripts unknown. Here, we have quantified RNA copies/ng cDNA (RNA cpn) for CYP1A1 and CYP1B1, as well asNad(p)hquinone oxidoreductase 1 (NQO1), which may reduce formation of BPdG adducts, using primary normal human mammary epithelial cell (NHMEC) strains, and the MCF-7 breast cancer cell line. In unexposed NHMECs, basal RNA cpn values were 58-836 for CYP1A1, 336-5587 for CYP1B1 and 5943-40112 for NQO1. In cells exposed to 4.0 µM BP for 12h, RNA cpn values were 251-13234 for CYP1A1, 4133-57078 for CYP1B1 and 4456-55887 for NQO1. There were 3.5 (mean, range 0.2-15.8) BPdG adducts/10(8) nucleotides in the NHMECs (n = 16), and 790 in the MCF-7s. In the NHMECs, BP-induced CYP1A1 RNA cpn was highly associated with BPdG (P = 0.002), but CYP1B1 and NQO1 were not. Western blots of four NHMEC strains, chosen for different levels of BPdG adducts, showed a linear correlation between BPdG and CYP1A1, but not CYP1B1 or NQO1. Ethoxyresorufin-O-deethylase (EROD) activity, which measures CYP1A1 and CYP1B1 together, correlated with BPdG, but NQO1 activity did not. Despite more numerous levels of CYP1B1 and NQO1 RNA cpn in unexposed and BP-exposed NHMECs and MCF-7cells, BPdG formation was only correlated with induction of CYP1A1 RNA cpn. The higher level of BPdG in MCF-7 cells, compared to NHMECs, may have been due to a much increased induction of CYP1A1 and EROD. Overall, BPdG correlation was observed with CYP1A1 protein and CYP1A1/1B1 enzyme activity, but not with CYP1B1 or NQO1 protein, or NQO1 enzyme activity.

Project description:Alcoholism and cigarette smoking are pervasive problems that have been implicated in human health. In this study, independent and combinative toxicities of alcohol and benzo(a)pyrene (BaP) were tested for reproductive toxicity in rats. Male Wistar rats were exposed to BaP (100 ?g per kg body weight) on alternative days and alcohol (2 g per kg body weight per day) daily, either individually or in combination for 60 days. Exposure to BaP or alcohol significantly decreased the fertility index and reduced the number of implantations associated with elevated pre- and post-implantation losses. The relative weights of testes, epididymis, seminal vesicles, and prostate gland were significantly decreased in BaP or alcohol administered rats. Exposure to BaP or alcohol significantly decreased daily sperm production, sperm density, percentages of motile, viable, HOS-tail swelled sperm, testicular 3?- and 17?-hydroxysteroid dehydrogenase activity levels, mRNA levels of steroidogenic acute regulatory protein, and serum testosterone levels. Further, in silico studies revealed the binding of BaP at the hydrophobic tunnel of StAR protein. Additional studies disclosed stable interactions of BaP with the amide group of ASN150 and the hydroxyl group of THR263 by forming three hydrogen bonds. Our results also showed that treatment of rats with BaP or alcohol caused a marked increase in levels of superoxide anions, hydrogen peroxide, and lipid peroxidation in testis and epididymis. Conversely, glutathione levels and activity levels of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase in testis as well as epididymis decreased significantly in the experimental rats. Under the same conditions, increased fragmented DNA levels were observed in sperm. The results of the present study indicate that exposure to BaP or alcohol adversely affected the male reproductive functions, which may be, at least in part, due to androgen deficiency and/or oxidative stress-related mechanisms. Consistently, the present results also showed higher reproductive toxicity upon exposure to combinations of BaP and alcohol than upon their individual treatments. Therefore, this combination was classified as additive and synergistic responses of BaP and alcohol.

Dataset Information

Khellinoflavanone, a Semisynthetic Derivative of Khellin, Overcomes Benzo[a]pyrene Toxicity in Human Normal and Cancer Cells That Express CYP1A1.

Publications

Khellinoflavanone, a Semisynthetic Derivative of Khellin, Overcomes Benzo[<i>a</i>]pyrene Toxicity in Human Normal and Cancer Cells That Express CYP1A1.

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