Steroid metabolism by rat nasal mucosa: Studies on progesterone and testosterone

doi:10.1016/0022-4731(84)90358-3

Journal of Steroid Biochemistry

Volume 20, Issue 5, May 1984, Pages 1147-1151

https://doi.org/10.1016/0022-4731(84)90358-3 Get rights and content

Abstract

The metabolism of [4-¹⁴C]progesterone and [4-¹⁴C]testosterone by slices of the nasal mucosa from rats was studied. As shown by gas chromatography-mass spectrometry there was a preferential formation of reduced progesterone-metabolites (5α-pregnane-3, 20-dione, 3α- and 3β-hydroxy-5α-pregnane-20-one, 20α- and 20β-hydroxypregn-4-en-3-one, 2α, 3α-dihydroxy-5α-pregnane-20-one, 3α, 16α-dihydroxy-5α-pregnane-20-one) and reduced testosterone-metabolites (4-androstene-3, 17-dione, 5α-dihydrotestosterone, 3α-hydroxy-5α-androstane-17-one, and 5α-androstane-3α, 17β-diol, 2α-hydroxy-5α-dihydrotestosterone, 5α-androstane-2α, 3α, 17β-triol) indicating the presence of 5α-reductase, 3α-, 3β-, 17β-, 20α- and 20β-hydroxysteroid oxidoreductase activities in this tissue. Progesterone-metabolites hydroxylated at positions 2α, 6α, 6β, 15α and 16α and testosterone-metabolites hydroxylated at positions 1β, 2α, 6β, 15β and 16α were also identified, indicating the presence of several steroid hydroxylases in the nasal mucosa. Autoradiography of the nasal region of rats injected with [4-¹⁴C]progesterone or [4-¹⁴C]testosterone showed a selective localization of radioactivity in the mucosa covering the olfactory region of the nasal cavity.

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Citation Excerpt :
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Neurosteroids hold great promise for the treatment of diseases of the central nervous system (CNS). We compared the uptake by 11 brain regions and appearance in blood of tritium-labeled pregnenolone and progesterone after intranasal and intravenous (IV) injection. Both neurosteroids appeared in blood and brain after either method of administration, but with important differences in uptake. Bioavailability based on appearance in arterial serum showed that about 23% and 14% of the intranasal administered doses of pregnenolone and progesterone, respectively, entered the blood. Brain levels were about two fold lower after intranasal administration for the two neurosteroids. With intranasal administration, brain levels of the two steroids did not vary over time (2–120 min), whereas brain levels were higher early (10 min or less) after i.v. administration. With i.v. administration, uptake by brain regions did not vary, whereas the olfactory bulb, hippocampus, and hypothalamus had high uptake rates after intranasal administration. Intranasal administration of prenenolone improved memory, whereas progesterone decreased anxiety, thus demonstrating that therapeutic levels of neurosteroids can be delivered to the brain by intranasal administration. The neurosteroids were rapidly degraded after i.v. or intranasal delivery, but pregnenolone was more resistant to degradation in the brain after intranasal administration and in serum after i.v. administration. These results show that either the i.v. or intranasal routes of administration can deliver neurosteroids to blood and brain, but that the two routes have significant differences with intranasal administration favoring some brain regions.
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To better understand the molecular relationship between contaminant exposure in Atlantic salmon and the cytochrome P450 system, we have cloned a CYP1A gene using reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE). The cloned cDNA possesses all characteristic motifs of teleost CYP1A genes including the start codon, heme-binding region, stop codon, and poly-adenylation signal. The cloned gene is also characterized by an extended 3′ untranslated region (UTR; 1025bp) containing three AUUUA sequences that are likely to be a target for rapid degradation of its mRNA. Its coding region (1569 base pairs) shares 97.4% and 96.7% sequence identity with the corresponding regions of rainbow trout CYP1A1 and CYP1A3 genes, respectively. In addition, the deduced amino acid sequence of salmon CYP1A shows 96.9% and 96.2% identity with rainbow trout P450 1A1 and P450 1A3 enzymes, respectively. Phylogenetic analysis of a sample of CYP genes confirmed that Atlantic salmon CYP1A is closely related to rainbow trout CYP1A genes as well. Northern analysis showed that CYP1A mRNA is at a significantly higher level in the liver of Atlantic salmon injected intraperitoneally with β-Naphthoflavone (BNF), suggesting that this gene is inducible. Southern analysis verified the presence of at least one copy of the CYP1A gene in the genomic DNA of Atlantic salmon. These results reveal the transcriptional and inductive properties of an Atlantic salmon CYP1A gene with an extended 3′ UTR, and provide molecular tools for studying the effects of xenobiotics on Atlantic salmon populations.
Binding of the pheromonal steroid, 5α-androst-16-en-3-one, to membrane-enriched fractions of boar and rat olfactory epithelium; Preliminary evidence for binding protein being a glycoprotein
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A high degree of binding of 5α-[ $^{3} H$ ]-androstenone was recorded in membrane-enriched fractions of porcine olfactory tissue. The specific (i.e. high affinity, low capacity) binding had a mean K_a approximately 2×10⁸ M⁻¹. A Hill plot of the data showed a Hill coefficient of approximately 2, possibly suggesting co-operativity of binding, with binding constants increasing from 8×10⁷ to 1.6×10⁹ M⁻¹ with increasing substrate concentration. The level of specific binding of 5α-[ $^{3} H$ ]-androstenone was nearly 10-fold higher than in corresponding respiratory tissue preparations and was markedly reduced in the presence of excess (approximately 1 μM) unlabelled 5α-androstenone. Corresponding fractions derived from rat olfactory tissue showed only 25% of the binding recorded for the pig.
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Journal of Steroid Biochemistry

Abstract

References (20)

Nucleus-associated steroid 5α-reductase activity and androgen responsiveness. A study in various organs and brain regions of rats

J. steroid Biochem.

Metabolism of testosterone in the isolated perfused rat lungs

J. steroid Biochem.

Metabolism of progesterone in the isolated perfused rat lungs

J. steroid Biochem.

Steroid hydroxylations catalyzed by cytochrome P-450

Studies on the metabolism of the odoriferous ketones 5α-androst-16-en-3-one and 4, 16-androstadien-3-one by the nasal epithelium of mature and immature sow

Biochim. biophys. Acta

Biochemical studies on the boar pheromones, 5α-androst-16-en-3-one and 5α-androst-16-en-3α-ol, and their metabolism by olfactory tissue

Cytochrome P-450 dependent monooxygenase activity in rat nasal epithelial membranes

Toxicol. Lett.

In vitro metabolism of 4-androstene-3, 17-dione and testosterone by rat submaxillary gland

Steroids

The distribution of labelled testosterone in mice

Acta endocr., Copenh.

Autoradiographic studies of labelled 5α-dihydrotestosterone in mice

Steroids Lipids Res.

Cited by (34)

Chemosignals and hormones in the neural control of mammalian sexual behavior

Brain distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration

Cloning of CYP1A in Atlantic salmon (Salmo salar)

Binding of the pheromonal steroid, 5α-androst-16-en-3-one, to membrane-enriched fractions of boar and rat olfactory epithelium; Preliminary evidence for binding protein being a glycoprotein

Cytochrome P450 and steroid hydroxylase activity in mouse olfactory and vomeronasal mucosa

Effects of physicochemical properties and other factors on systemic nasal drug delivery