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Biomedical subjects

M R Juchau

Publications and source records attributed to M R Juchau.

At least 19 recordsLinked to original sources
PubMed1995

Biotransformation of all-trans-retinol and all-trans-retinal to all-trans-retinoic acid in rat conceptal homogenates.

Catalysis of the oxidation of all-trans-retinol (vitamin A1) or of all-trans-retinal to all-trans-retinoic acid (all-trans-RA) by rat conceptal enzymes was investigated during organogenesis. Products of the reaction were identified and quantified with HPLC by comparing their elution times with those of authentic standard retinoids. Under the incubation and assay conditions utilized, all-trans-retinol and all-trans-retinal were converted to readily detectable quantities of all-trans-RA. Rat conceptal homogenates from gestational days 10.5, 11.5 and 12.5 each exhibited enzymatic activity for oxidation of all-trans-retinol and all-trans-retinal to all-trans-RA. Enzymatic catalysis was verified by showing that: (1) both reactions were coenzyme dependent; (2) the rates of reactions increased as concentrations of conceptal protein increased; (3) both reactions were abolished by heating the tissue homogenates (100 degrees, 5 min); and (4) both reactions exhibited substrate saturation. Under the same experimental conditions, formation of all-trans-RA from all-trans-retinol was much slower than from all-trans-retinal, suggesting that oxidation of all-trans-retinol to all-trans-retinal was the rate-limiting step for biotransformation of all-trans-retinol to all-trans-RA in embryonic tissues. When NAD or NADP were replaced by NADH or NADPH, the rate of oxidation of all-trans-retinol was reduced markedly, indicating that the reaction was catalyzed primarily by an NAD/NADP-dependent dehydrogenase(s). Carbon monoxide (CO:O2 = 90:10) did not inhibit the reaction. NAD appeared to be a more effective cofactor than NADP in catalyzing oxidation of all-trans-retinal to all-trans-RA. When NAD was omitted, formation of all-trans-RA from all-trans-retinal was reduced by approximately 55%. Replacing NAD by NADH or NADPH also reduced the conversion of all-trans-retinal to all-trans-RA by about 60%. These observations suggested at least two pathways for the generation of all-trans-RA from all-trans-retinal in embryos: oxidation catalyzed by an NAD/NADP-dependent dehydrogenase(s) and oxidation catalyzed by an oxidase(s) that did not require NAD, NADH, NADP or NADPH. Conversion of all-trans-retinol to all-trans-RA was inhibited strongly by low concentrations of citral, but not by high concentrations of sodium azide, 4-methylpyrazole, or metyrapone. Similarly, oxidation of all-trans-retinal was inhibited strongly by citral but not by metyrapone.(ABSTRACT TRUNCATED AT 400 WORDS)

Acyclic Monoterpenes↗
PubMed1995

Expression of functional cytochrome P4501A1 in human embryonic hepatic tissues during organogenesis.

Investigations with chemical inhibitors and with inhibitory antibodies specific for cytochrome P4501A-catalyzed ethoxyresorufin (ethoxyphenoxazone) O-deethylation and 2-acetylaminofluorene (N-2-fluorenylacetamide) ring hydroxylation indicated that cytochrome(s) P450 of the 1A subfamily was functionally expressed in human embryonic hepatic tissues at very early stages (days 50-60) of gestation. Lack of detectable capacity of hepatic microsomal enzymes to catalyze either N-hydroxylation of 2-acetylaminofluorene or O-demethylation of methoxyresorufin indicated that functional cytochrome P4501A2 is expressed minimally or negligibly in human embryonic hepatic tissues. By contrast, profound inhibition of the ring hydroxylation of 2-acetylaminofluorene and of the O-deethylation of ethoxyresorufin by 7,8-benzoflavone as well as by anti-cytochrome P4501A1 antibodies indicated the presence of significant levels of functional cytochrome P4501A1 in hepatic microsomes of human embryos. Using the reverse transcriptase-linked polymerase chain reaction with specific oligonucleotide primers, we also detected significant expression of cytochrome P4501A1 mRNA in human embryonic livers. Polymerase chain reaction amplification, cloning and sequencing of the corresponding cDNA provided evidence that the cytochrome P4501A1 mRNA expressed in human embryonic tissues was identical to that expressed in adult human tissues. The results of the study have important implications in terms of the embryotoxic effects of chemicals that are known to be substrates, inhibitors or inducers of cytochrome P4501A1 and to which pregnant women are exposed.

2-Acetylaminofluorene↗
PubMed1995

Xenopus laevis: a model system for the study of embryonic retinoid metabolism. I. Embryonic metabolism of 9-cis- and all-trans-retinals and retinols to their corresponding acid forms.

Recently, the temporal and spatial distribution patterns of two established, endogenous retinoid receptor ligands, 9-cis-retinoic acid and all-trans-retinoic acid and various precursor retinoids were described in Xenopus embryos during early development (Creech Kraft et al., Proc. Natl. Acad. Sci. U.S.A. 1994; Biochem. J. 1994). Each of these two receptor ligands is a metabolite of vitamin A (all-trans-retinol), and each is also a potent dysmorphogen in Xenopus embryos as well as in embryos of several other vertebrate species. This study demonstrates early embryonic metabolism of exogenous all-trans-retinol, 9-cis-retinol, all-trans-retinal, and 9-cis-retinal to 9-cis-retinoic acid, all-trans-retinoic acid, and other metabolites in Xenopus embryos during neurulation, a specific stage of development that spans a time period of approximately 8 hr. Our results demonstrate that the Xenopus embryo provides a suitable model system for studying the embryonic bioconversion of retinoids and dysmorphogenic effects within a single time window of development.

Abnormalities, Drug-Induced↗
PubMed1995

Xenopus laevis: a model system for the study of embryonic retinoid metabolism. II. Embryonic metabolism of all-trans-3,4-didehydroretinol to all-trans-3,4-didehydroretinoic acid.

This study demonstrates early embryonic metabolism of exogenous all-trans-3,4-didehydroretinol (vitamin A2) to all-trans-3,4-didehydroretinal and to all-trans-3,4-didehydroretinoic acid in Xenopus embryos during neurulation. The latter metabolite was recently shown to bind with high affinity and to activate various retinoic acid receptors. Embryos treated with all-trans-3,4-didehydroretinol during early or late gastrulation exhibited abnormalities along the anteroposterior axis. The abnormalities were primarily in the posterior regions of the embryo, with only minor defects anteriorally. Eye malformations, typical for early exposure to 9-cis- and all-trans-retinols and retinals (companion paper), were not observed. We also present evidence that all-trans-3,4-didehydroretinoic acid is present endogenously during early neurulation and is evenly distributed along the anteroposterior axis. After treatment with all-trans-3,4-didehydroretinol, embryonic levels of all-trans-3,4-didehydroretinoic acid exceeded endogenous levels of this metabolite during early and late neurulation. We hypothesize that the dysmorphogenic effects produced by treatment of Xenopus embryos with the alcohol precursor, all-trans-3,4-didehydroretinol, are the result of its embryonic conversion to its corresponding acid ligand.

Abnormalities, Drug-Induced↗
PubMed1994

Induction in vitro and complete coding region sequence of cytochrome P4501A1 cDNA from cultured whole rat conceptuses during early organogenesis.

Exposures of cultured whole rat conceptuses during organogenesis to 3-methylcholanthrene (MC; 0.025-25 microM), 5,6-benzoflavone (BNF; 5-100 microM) or benz[a]anthracene (BA; 5-100 microM) were effected by placement of each of these "MC-type" inducing agents in the culture medium at the time of explantation on day 9.5 of gestation. Conceptuses were then cultured for 48 hr and evaluated on day 11.5 for increased expression of inducible conceptal cytochrome P450 (P450). The three agents each elicited concentration-dependent increases in 7,8-benzoflavone (ANF)-inhibitable ethoxyresorufin O-deethylase (EROD) activities and increased P4501A1 mRNA as detected by primer-specific reverse transcriptase-polymerase chain reaction (RT-PCR) in cell-free preparations of the treated, cultured conceptuses. At effective inducing concentrations, dysmorphogenic or other embryotoxic effects were not detectable. At 20 microM concentrations, the three agents exhibited roughly equal induction that was approximately equivalent in magnitude (6- to 13-fold) to that achieved previously with exposures to MC in utero. Additions to the culture medium of 2.5 to 10 microM concentrations of dexamethasone (DEX) did not alter significantly the magnitude of MC-elicited induction in vitro. Repeated full-length sequencing of an RT-PCR-amplified cDNA revealed a coding region sequence identical to that reported for the P4501A1 sequence from adult rat liver. The results provide a basis for investigations, in the absence of maternal influences, of the regulation of mammalian conceptal P4501A1 in intact tissues during organogenesis, a gestational period critical in terms of the dysmorphogenic and other embryotoxic effects of foreign organic chemicals. The results are also pertinent to studies of embryotoxicity, particularly to the transplacental carcinogenicity, mutagenicity and dysmorphogenicity of P4501A1 substrates.

Animals↗
PubMed1994

Temporal distribution, localization and metabolism of all-trans-retinol, didehydroretinol and all-trans-retinal during Xenopus development.

Recently, the temporal and spatial distribution patterns of the retinoid receptor ligands 9-cis-retinoic acid and all-trans-retinoic acid were described in Xenopus embryos during early development [Creech Kraft, Schuh, Juchau and Kimelman (1994) Proc. Natl. Acad. Sci. U.S.A., in the press]. The present study demonstrates the presence and distribution of their likely precursors, all-trans-retinol, didehydroretinol, didehydroretinal and all-trans-retinal, as well as the occurrence of 4-oxo metabolites, in Xenopus embryos. The temporal and spatial distribution patterns of all-trans-retinol, didehydroretinol and all-trans-retinal did not coincide with that observed for 9-cis-retinoic acid but, in certain regards, were similar to the patterns delineated for all-trans-retinoic acid and all-trans-retinoyl beta-glucuronide. Evidence is presented that 9-cis-retinoic acid can be synthesized from both all-trans-retinoic acid and all-trans-retinol in Xenopus embryos, suggesting that the difference between the distributions of 9-cis-retinoic acid and the other retinoids may be caused by selective synthesis and/or protein binding of the 9-cis isomer.

Animals↗
PubMed1994

Dysmorphogenic effects of nitric oxide (NO) and NO-synthase inhibition: studies with intra-amniotic injections of sodium nitroprusside and NG-monomethyl-L-arginine.

Sodium nitroprusside (SNP), a chemical that is readily converted to nitric oxide (NO) in biological systems, was microinjected into the amniotic fluids of cultured whole rat conceptuses on day 10.5 of gestation and dysmorphogenic/embryotoxic effects were evaluated after a 24 hr incubation period. Injections of 217 ng/embryo (approximately 800 microM) resulted in whitened zones of dead cells in a discretely circumscribed region within the mesencephalon closely associated with the neural tube. These zones were observed with a high incidence after SNP microinjections and were referred to as "white caps" because of their microscopic appearance. At higher concentrations, the whitened zone extended into the rhombencephalon and occasionally appeared to extend the full length of the dorsal midline. The whitened zones of tissue separated readily from the apparently normal underlying tissues upon removal or disturbance of the amniotic membrane. Coinjection of ferrous hemoglobin with SNP selectively prevented the appearance of "white caps" but not other embryotoxic manifestations. Microinjections of the breakdown products of light-exposed SNP elicited generalized embryotoxicity but "white caps" were not observed. In separate experiments, we found that embryonic enzymes catalyzed significant conversion of arginine to citrulline, indicating expression of NO-synthase during organogenesis. NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO-synthase, was microinjected (50-150 ng/embryo; approximately 200-600 microM) on day 10.5 of gestation and produced malformations that differed markedly from those elicited by SNP. Failure of anterior and posterior neural tube closure and profound underdevelopment of the hyoid arch and optic cup were observed at concentrations that produced no apparent growth deficit. These studies with SNP and L-NMMA indicated that both an excess and a deficiency of NO can be embryotoxic/dysmorphogenic and suggest important roles for optimal levels of NO and NO synthases in normal embryonic development.

Amino Acid Oxidoreductases↗
PubMed1994

Benzene and benzene metabolites as embryotoxic agents: effects on cultured rat embryos.

Benzene and several of its metabolites were investigated for dysmorphogenic and embryotoxic effects after direct exposures of cultured whole rat conceptuses. Benzene produced no statistically significant effects at concentrations up to 1.6 mM. Inclusion with 1.6 mM benzene of an hepatic xenobiotic-biotransforming system (S9) resulted in only minor decreases in embryonic growth parameters and no detectable dysmorphogenesis. Phenol, a major benzene metabolite, also elicited only minimal embryotoxicity at 1.6 mM concentrations. However, inclusion of an S9 system with phenol resulted in significant dysmorphogenic and embryotoxic effects at concentrations as low as 0.01 mM. For phenol bioactivation, S9 from phenobarbital-induced rats was the most effective, with induction by pregnenolone-16 alpha-carbonitrile, isopropanol, Aroclor 1254, no inducer, and 3-methylcholanthrene following in order of effectiveness. Bioactivating activity resided solely in the microsomal fraction. Metabolites coeluting on HPLC with hydroquinone and catechol were the major metabolites generated from phenol by each S9 system, but no significant correlation between specific metabolite generation and embryotoxicity was apparent. Of the benzene metabolites studied, trans, trans-muconaldehyde exhibited the highest embryotoxic potency but was not detectably generated by any of the S9 systems. Hydroquinone, catechol, and benzoquinone were approximately equipotent, each producing 100% lethality at 0.1 mM. Combined additions to the culture medium of hydroquinone together with phenol resulted in greater than additive effects, indicating a possible synergistic interaction between these metabolites and suggesting that peroxidase activity may be important to the mechanism of phenol-elicited embryotoxicity.

Animals↗
PubMed1994

Functional cytochrome P4503A isoforms in human embryonic tissues: expression during organogenesis.

Expression of functional cytochrome P450 (CYP) isoforms in human embryonic tissues was explored during organogenesis (days 50-60 of gestation) with substrate probes, inhibitor probes, and immunoprobes and by reverse transcription-polymerase chain reaction (PCR), cloning, and sequencing. Evidence was obtained for the presence of relatively high levels of one or more functional CYP3A isoforms in embryonic livers. This was manifested as relatively extensive hydroxylation of (R)-warfarin at carbon 10 and as triacetyloleandomycin-inhibited O-debenzylation of benzyloxyresorufin when human embryonic hepatic microsomal fractions were used as enzyme sources. Immunoblots with anti-CYP3A4 antibody exhibited a strong signal in embryonic hepatic tissues but, in contrast, indicated very low or negligible CYP3A levels in human embryonic lung, kidney, heart, adrenal, and brain tissues. To explore expression of individual members of the CYP3A subfamily in human embryonic hepatic tissues at this early gestational stage, CYP3A cDNA was generated by reverse transcription, amplified by PCR, cloned, and sequenced. Oligonucleotide primers used for PCR were designed to flank target sequences unique to CYP3A but also common to all human CYP3A subfamily members for which GenBank nucleotide sequence information was available (CYP3A3, CYP3A4, CYP3A5, CYP3A5P, and CYP3A7). Sequencing data indicated that plasmids in 58 of 59 recombinant positive colonies contained an insert with a sequence identical to that present in CYP3A7 cDNA and the plasmid of only one colony contained an insert with a sequence identical to that present in CYP3A5 cDNA. No evidence was found for expression of CYP3A3 or CYP3A4. Thus, during organogenesis, human embryonic hepatic tissues express primarily CYP3A7 and are capable of significant CYP3A7-catalyzed xenobiotic monooxygenation during this very early stage of gestation.

Base Sequence↗
PubMed1993

9-cis-retinoic acid: a direct-acting dysmorphogen.

Experiments in vitro with cultured rat conceptuses demonstrated that 9-cis-retinoic acid (9-cis-RA) (300 ng/mL amniotic fluid) produced branchial arch and somite defects similar to those elicited by equal concentrations of all-trans-retinoic acid (all-trans-RA), but with an increase in cephalic defects that included missing optic vesicles. After conceptuses were intraamniotically microinjected with 600 ng 9-cis-RA/mL amniotic fluid on day 10 of gestation, an unusual heart defect was also observed. HPLC analyses indicated that 9-cis-RA readily underwent conversion to the less active metabolite, 13-cis-retinoic acid (13-cis-RA), in cultured conceptuses during the first 4 hr after treatment but only after 6 hr could elevated levels of the potent dysmorphogen all-trans-RA be detected. In separate experiments, conversion of 13-cis-RA or of all-trans-RA to 9-cis-RA could not be detected during a 6-hr embryo culture period. Endogenous levels of 9-cis-RA in whole rat embryos also were below limits of detection but small quantities of this isomer could be detected in neonatal rat eye and human embryonic brain. Our present study strongly suggests that 9-cis-RA is a direct-acting dysmorphogen with probable specific target sites of action.

Animals↗
PubMed1993

In vitro embryotoxicity of N-methyl-N-(7-propoxynaphthalene-2-ethyl)hydroxylamine (QAB): evidence for N-dehydroxylated metabolite as a proximate dysmorphogen.

The rat conceptus biotransforms N-methyl-N-(7-propoxynaphthalene-2-ethyl)hydroxylamine (QAB) in vitro to 7-propoxynaphthalen-2-ylacetic acid (QAA) and six more (M1 to M6) metabolites. Thus far, M4 has been identified as N-demethyl-QAB and M6 as N-desoxy-QAB. We investigated which of these two metabolites might be involved in QAB-embryotoxicity in vitro. Conceptuses were cultured from day 9.5 to 11.5 post-coitum, and were exposed to N-demethyl-QAB or N-desoxy-QAB either in the culture medium or by microinjection directly into the amniotic cavity. When added to the culture medium, N-demethyl-QAB (No Observed Adverse Effect Level, NOAEL, for growth 122 microM and for differentiation 41 microM) was less active than QAB itself (NOAEL for growth and differentiation 12 microM). N-desoxy-QAB caused severe growth retardation and an impairment of differentiation at a concentration of 11 microM (NOAEL 3.6 microM). As regards causing anomalies, the NOAEL of N-demethyl-QAB (41 microM) was 10-fold higher than that of QAB (NOAEL 3.9 microM) and that of N-desoxy-QAB (NOAEL 3.6 microM). At an intraamniotic concentration of 0.7 mM, N-demethyl-QAB caused no effects on growth and differentiation and no increase of anomalies was observed, whereas QAB and N-desoxy-QAB each elicited an increase in dysmorphogenic embryos at equimolar concentrations without affecting growth and differentiation. It is, therefore, concluded that N-desoxy-QAB, but not N-demethyl-QAB, could be a proximate dysmorphogen responsible for the embryotoxicity/teratogenicity of QAB in vitro.

Abnormalities, Drug-Induced↗
PubMed1993

Chemical teratogenesis.

This review has briefly summarized what is currently known concerning the mechanisms whereby several groups of chemicals regarded as "recognized" human teratogens elicit their respective teratogenic effects. It is evident that the extent of our understanding of mechanisms for individual chemicals varies dramatically from that of a reasonably good understanding for methotrexate and other folic acid antagonists to that of virtually no understanding for the most widely recognized human teratogen, thalidomide. Even with methotrexate, however, much remains to be learned pertaining to mechanisms--i.e., the critical links in the chain of events between dihydrofolate reductase inhibition and the manifestation of specific abnormalities. Nevertheless, we can take some comfort in being able to say that we understand the primary causative mechanism. For thalidomide, as well as several others the chemical represents both a shame and a challenge--a challenge that should be addressed with our most serious efforts.

Abnormalities, Drug-Induced↗
PubMed1993

Tissue levels of retinoids in human embryos/fetuses.

In nonhuman vertebrate embryos, two endogenous retinoids with significant morphogenic activities have been identified thus far: all-trans retinoic acid and 3, 4-didehydroretinoic acid. To date, no information is available concerning endogenous retinoid levels in developing human embryos or fetuses. The purpose of the present study was to provide data relating to normal levels of retinoids in various human embryonic and fetal tissues at various stages of gestation measurable with HPLC techniques. Our investigations show that all-trans-retinoic acid, 13-cis-retinoic acid, retinol, all-trans-retinoyl-beta-glucuronide, and one unidentified metabolite were all present and quantifiable in several human embryos and fetuses investigated. Tissue levels of retinol were consistently much higher than those of the other three detected metabolites; 4-oxo metabolites were below the levels of detection in all samples studied.

Brain Chemistry↗
PubMed1992

Conceptual biotransformation of 4-oxo-all-trans-retinoic acid, 4-oxo-13-cis-retinoic acid and all-trans-retinoyl-beta-glucuronide in rat whole embryo culture.

In cultured rat conceptuses, intraamniotic microinjections of 2500 ng/mL of 4-oxo-13-cis-retinoic acid, 600 ng/mL 4-oxo-all-trans-retinoic acid or 4000 ng/mL all-trans-retinoyl-beta-glucuronide, produce qualitatively and quantitatively similar patterns of dysmorphogenesis as those reported after the intraamniotic microinjection of 250 ng/mL all-trans-retinoic acid [Lee et al., Teratology 44: 313-323, 1991; Creech Kraft et al., Teratology 45: 259-270, 1992]. In the present study, we utilized HPLC techniques to analyze retinoid levels in cultured rat conceptuses, 1.5 hr after intraamniotic microinjections of 4-oxo-13-cis-retinoic acid (2500 ng/mL), 4-oxo-all-trans-retinoic acid (600 ng/mL) or all-trans-retinoyl-beta-glucuronide (4000 ng/mL). Our findings show that, after the microinjections of 4-oxo-all-trans-retinoic acid or 4-oxo-13-cis-retinoic acid (at these selected concentrations), 4-oxo-all-trans-retinoic acid was predominant in the embryos proper at concentrations of about 200 nM. This was roughly equivalent to the levels of all-trans-retinoic acid assayed after microinjections of all-trans-retinoyl-beta-glucuronide (4000 ng/mL). We conclude from these studies that both 4-oxo-all-trans-retinoic acid and all-trans-retinoic acid behave as ultimate or proximate dysmorphogens.

Animals↗
PubMed1992

Microinjections of cultured rat conceptuses: studies with 4-oxo-all-trans-retinoic acid, 4-oxo-13-cis-retinoic acid and all-trans-retinoyl-beta-glucuronide.

4-Oxo-all-trans-retinoic acid, 4-oxo-13-cis-retinoic acid and all-trans-retinoyl-beta-glucuronide were intraamniotically microinjected in rat embryos on day 10 of gestation and cultured until day 11.5. A comparison of the concentration-effect relationships showed that the dysmorphogenic effects produced by these metabolites were qualitatively similar to those of parent all-trans-retinoic acid. Compared with all-trans-retinoic acid (300 ng/ml), the dysmorphogenic effects were elicited by a 2-fold higher concentration of 4-oxo-all-trans-retinoic acid, an approximately 10-fold higher concentration of 4-oxo-13-cis-retinoic acid and a 16-fold higher concentration of all-trans-retinoyl-beta-glucuronide. A surplus of uridine 5'-diphospho-glucuronic acid, microinjected together with 300 ng/ml all-trans-retinoic acid, decreased the observed embryo-toxicity of all-trans-retinoic acid, suggesting the possibility of glucuronidation in tissues of the conceptus per se. The results of the study provide further support for the hypothesis that 4-oxo-all-trans-retinoic acid and all-trans-retinoic acid are, in contrast to the corresponding cis-isomers and glucuronides, ultimate dysmorphogenic retinoids.

Amnion↗
PubMed1992

Mechanisms of glucagon-induced increases in rates of cytochrome P450-dependent pentoxyphenoxazone O-depentylation in cultured rat conceptuses.

Inclusions of glucagon (1.0 or 2.0 microM, final concentrations) in the media of cultured whole rat conceptuses resulted in concentration-dependent increases in measured rates of O-depentylation of pentoxyphenoxazone in cell-free preparations of conceptal tissues. Enzymic activities were assayed 24 h after initial exposure of the conceptuses to glucagon on day 10 of gestation. Glucagon elicited increases in tissue levels of cAMP that were parallel to those produced by 3-isobutyl-1-methylxanthine over the same time period. Tissue cAMP levels were maximal after 2 h, rapidly returned to control levels and were also equal to background levels in controls after the 24 h culture period. Dibutyryl cAMP, 3-isobutyl-1-methylxanthine, theophylline, and RO201724, a cAMP-selective phosphodiesterase inhibitor, each produced 75 to 100% increases in O-dealkylase activity. Dibutyryl cGMP and two phosphodiesterase inhibitors, enoximone (cGMP-inhibited) and zaprinast (cGMP-specific), each failed to produce statistically significant increases in O-depentylase activity. The O-depentylase was tentatively identified as a conceptus-specific P450 cytochrome that is synthesized predominantly in tissues of the visceral yolk sac. The results indicated that glucagon may upregulate a unique, xenobiotic-biotransforming P450(s) via a long-term mechanism(s) specifically involving tissue cAMP.

Animals↗