1452. Effect of Drugs Active on Mammalian Estradiol (E) Receptors (r) on Paracoccidioides brasiliensis (Pb) Mycelial-to-Yeast Conversion (M-Y)
Session: Poster Abstract Session: Fungal Infections
Saturday, October 5, 2013
Room: The Moscone Center: Poster Hall C
Background: We have shown E blocks Pb conidia- or M-Y in vitro or vivo, which would explain resistance of females to Pb disease; that there is a high affinity binding protein (BP) for E in Pb cytosol at 0oC, and concurrently another, low affinity BP at 37oC; and that Pb genes analogous to mammalian E signaling and transcription pathways are regulated during E block of M-Y. Diethylstilbestrol and tamoxifen are weak competitors for BP and have small to no effect on M-Y, compared to their effects on mammalian Er.

Methods: We studied E;  fulvestrant (F), which binds mammalian E αr and βr, antagonist to E and downregulator of r, and mammalian membrane receptor (GPER) agonist, and G1, an E agonist that competes with E at GPER, not binding to αr or βr. Concentrations 10-6 to 10-8M alone, and ratios 10:1, 1:1, and 1:10 to E, were studied on M-Y over 12 days.

Results: (Table) In n=7 expts. E blocked M-Y. Alone, G1 resembled E agonist at high concs.; F had a small E-like effect and was not dose responsive. G1 had a small antagonistic effect on E at low (1:10) ratio, F a small antagonistic effect at the lowest and highest ratios. In 1 expt., diarylproprionitrile (D), a selective mammalian βr agonist had no effect on its own or on E effect.

Conclusion: These studies suggest Pb functional receptor may be most like GPER. Where lack of dose-responsiveness, it resembles the nonmonotonic and oscillating responses seen with E and xenoestrogens in mammalian cells, explainable by different receptor targets opposing each other, hormesis, or nongenomic E regulation of E metabolism enzymes. A complicating factor is a possible Pb ligand that could also bind to BPs and compete.

 

 

M-Y

M-Y

M-Y

Control

4+

4+

4+

Molar

10-6

10-7

10-8

E

0

0-tr

tr

G1

1+

4+

4+

F

3+

4+

3+

D

4+

4+

4+

Ratio

10:1

1:1

1:10

G1 & E

0

0-tr

1-2+

F & E

1-2+

0-tr

1-2+

D & E

0

0-tr

tr

Vicky Chen, BS1, Jata Shankar, PhD1,2, Karl V. Clemons, PhD1,2,3 and David A. Stevens, MD1,2,3, (1)California Institute for Medical Research, San Jose, CA, (2)Stanford Univ., Stanford, CA, (3)Santa Clara Vly. Med. Ctr., San Jose, CA

Disclosures:

V. Chen, None

J. Shankar, None

K. V. Clemons, None

D. A. Stevens, None

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