OK, medics, nurses and pharmacologists - If  I get the meaning of the article quoted below, the use of steroidal anti-inflamatory drugs to decrease pain may accelerate age related muscular atrophy, thus potentially increasing muscular pain, leading to increased use of anti-inflammatory drugs.

This follows from the inference that treatment of arthritic and other pain with steroidal anti-inflamatories has a strong likelyhood of producing elevated levels of "some forms of cytochrome  P450".    And that in turn ". . . myopathy may result from steroid induction of cytochrome P450 . . ."

The use of steroidal anti-inflamatory drugs  occurs most frequently in people of my age (64) and older, where musculature atrophy itself can result in sensations of muscular discomfort, achyness, and pain relief seeking behavior.

Yet, such treatment may  itself cause or accelerate  "myopathy" - muscular atrophy.

In prescribing steroidal anti-inflamatories for older patients, nominally for joint pain associated with arthritis, do medics generally thoroughly evaluate and attempt to differentiate between muscular pain associated with age related muscle loss and weakness and the pain associated with true bone and joint diseases?   Because if a person were to take these steroidal drugs to reduce muscle pain which has been mistaken for joint pain they might well worsen their condition, not make it better. 

Your  arguments in support of or against these inferences and conclusions, if you care to provide them, will be appreciated.

Jim Pivonka
PO Box 751
La Crosse, KS  67548
http://www.jimpivonka.com
http://www.jimpivonka.com/unpublished/Steroidanti-painmedsCytochrom%20P450DHEA.html

CYTOCHROME P450 NOTE: The cytochrome p450 enzymes are  used by the liver in processing and eliminating foreign and toxic materials, including drugs, from the body.  That accounts for their importance in drug interactions, and in the effect of drugs on the liver itself. The fact that grapefruit juice is a P450 inhibitor is why drinking grapefruit juice adds to the effects of some drugs in the body - it slows the metabolization of those drugs by the P450 enzymes in the gut and liver.   On the other hand, the use of St. John's Wort as an herbal treatment for treatment accelerates the metabolization of some drugs thus reducing their effectiveness, because it activates (induces) cytochrome P450 enzyme pathways.  (SJW is also an MAO inhibitor, and cross drug reactions with and among MAO's is a problem in itself.) http://www.ama-assn.org/special/hiv/newsline/briefing/cytochro.htm http://www.geocities.com/hupiteekki/paihde01.htm http://www.aidsinfonyc.org/hivplus/issue1/ahead/p450.html Hyperactivation and/or suppression of various of P450 'pathways' resulting from exposure to military pathogens and anti-pathogens, as well as environmental warfare agents (Agent Orange, hydrocarbon aerosols, etc.)  are likely the cause of the unexplained disease syndromes experienced by Viet Nam and Gulf War veterans. The same would hold for the peculiar sets of symptoms and diseases presented by people living in areas of biological and chemical waste storage, spillage, and dumping.   And in fact one of the premier researchers of P450 enzyme activity, David J. Waxman,  is associated with the Superfund Basic Research Center at Boston University, NIH grant ES07381J.  Much of his research and publication deals  with P450 enzyme activity and its interactions with environmental contaminants.  An abstract of one of his papers, concluding with the statement "Consequently, P450 induction by xenobiotics may perturb endogenous regulatory circuits resulting in pathophysiological consequences. " is appended below. The fact that "59% of products cited in ADR studies are metabolised by polymorphic Phase I enzymes, the vast majority of these being from the cytochrome P450 family" is discussed and additional links to information about the CP450 family are provided at "Pharmacogenetics, Single Nucleotide Polymorphism, Adverse Drug Reactions, and the Cytochrome P450 Family" http://www.jimpivonka.com/unpublished/PharmacoGenetics-mchelsinki.html#CP450SNPs

Here is the quoted letter:

Critical Illness Myopathy, Steroids, and Cytochrome P450

Critical illness myopathy is a poorly understood, but increasingly recognized clinical syndrome that characteristically occurs in the intensive care unit among patients who have been treated with multiple drugs (particularly neuromuscular-blocking agents and antibiotics) and high-dose steroids.1-6 This rapidly progressive myopathy is characterized by muscle fiber atrophy and/or necrosis, often selectively affecting type2 myofibers (Figure).  Steroids are potent inducers of some forms of cytochrome  P450. 7

Recent studies8 suggest that cytochrome P450 is associated with skeletal muscle sarcoplasmic reticulum. Induction of cytochrome P450 and the consequent formation of reactive intermediates in the metabolism of some compounds result in the activation of calcium-release channels. 9

Critical illness myopathy may result from steroid induction of cytochrome P450 associated with sarcoplasmic reticulum.   The consequent production of reactive intermediate metabolites of other drugs given in the setting of critical illness then causes pathologic activation of calcium-release channels in sarcoplasmic reticulum and consequent muscle injury. The differences between muscle fiber types in calcium handling may account for the preferential involvement of type 2 muscle fibers in both steroid myopathy8 and critical illness myopathy.
 

Jack E. Riggs, MD
Sydney S. Schochet, Jr, MD
Departments of Neurology and Pathology
West Virginia University Health Sciences Center
Morgantown, WV 26506-9180

1. Chad DA, Laconis D. Critically ill patients with newly acquired weakness: the clinicopathological spectrum. Ann Neurol. 1994;35:257-259.
2. Al-Lonzi MT, Pestronk A, YeeWC,Flaris N, Cooper J. Rapidly evolving myopathy with myosin-deficient muscle fibers. Ann Neurol. 1994;35:273-279.
3. Ruff RL. Acute illness myopathy. Neurology. 1996;46:600-601.
4. Rich MM, Teener JW, Raps EC, Schotland DL, Bird SJ. Muscle is electrically inexcitable in acute quadriplegic myopathy.  Neurology. 1996;46:731-736.
5. Gutmann L, Blumenthal D, Gutmann L, Schochet SS. Acute type II myofiber atrophy in critical illness. Neurology.  1996;46:819-821.
6. Faragher MK, Day BJ, Dennett X. Critical care myopathy: an electrophysiological and histological study. Muscle Nerve.  1996;19:516-518.
7. Nebert DW, Adesnik M, Coon MJ, et al. The P450 gene superfamily: recommended nomemclature. DNA. 1987;6:1-11.
8. Crosbie SJ, Blain PG, Williams FM. An investigation into the role of rat skeletal muscle as a site for xenobiotic metabolism using microsomes and isolated cells. Hum Exp Toxicol. 1997;16:138-145.
9. Stoyanovsky DA, Cederbaum AI. Thiol oxidation and cytochrome P450-dependent metabolism of CCl4 trigers Ca2+ release from liver microsomes. Biochemistry. 1996;35:15839-15845.
 

David I. Waxman
Division of Cell and Molecular Biology
Department of Biology
Boston University
Boston, MA 02215

The biochemistry of foreign compound metabolism and the roles played by individual drug-metabolizing enzymes (DMEs) and their allelic variants in the detoxification of drugs and other xenochemicals is an important area of molecular pharmacology and toxicology that has been widely studied over the past decade. The emerging field of toxicogenomics, including the introduction of high throughput analyses based on DNA array technologies, has provided new mechanistic insights in toxicology and holds much promise as a new approach to identify potential toxic chemicals at an early stage in drug development. More traditional molecular studies have led to important advances in our understanding of the mechanisms through which foreign chemicals impact on xenobiotic metabolism with key discoveries of the mechanisms through which xenochemicals induce the expression of hepatic cytochromes P450 and other DMEs. Roles for three 'orphan' nuclear receptor superfamily members, designated CAR, PXR and PPAR, in respectively mediating the induction of hepatic P45Os belonging to gene families CYP2, CYP3 and CYP4 in response to the prototypical inducers phenobarbital (CAR), rifampkin (PXR)., and clofibrate (PPAR) have now been established [for review, see Waxman (1999) Arch Biochem Biophys 3~69:11-23). These three P450-regulatory nuclear receptors belong to the same nuclear receptor gene family (family NRI), share a common heterodimerization partner, retinoid X-receptor (RXR) and exhibit important species differences in ligand specificity that help explain species-specific patterns of P450 induction. These xeno-receptors also are subject to cross-talk interactions with other nuclear receptors and a broad range of other intracellular signaling pathways, including pathways involving cytoline and growth factor-activated STAT transcription factors. Endogenous ligands of the three xenobiotic-responsive nuclear receptors have been identified and physiological receptor functions are emerging, lending support to the proposal that an important biological function of these xeno-receptors is to modulate liver gene expression in response to endogenous hormonal stimuli. Consequently, P450 induction by xenobiotics may perturb endogenous regulatory circuits resulting in pathophysiological consequences. (Supported in part by Superfund Basic Research Center at Boston University, NIH grant ES07381J).
http://www.ems-us.org/gta/fallr00.html

Cytochrome P-450 mRNAs are modulated by dehydroepiandrosterone, nafenopin, and triiodothyronine.

Singleton DW, Lei XD, Webb SJ, Prough RA, Geoghegan TE.  Department of Biochemistry and Molecular Biology, University of Louisville, School of Medicine, Kentucky 40292, USA.

Dehydroepiandrosterone (DHEA) is the only known naturally occurring compound that promotes peroxisome proliferation in rodent liver, and stimulates transcriptional induction of genes involved in lipid metabolism and peroxisomal beta-oxidation. Therefore, we examined mRNA for several such genes in rat liver, specifically acyl-CoA oxidase and the cytochromes P-450 (CYP4A1, CYP4A3, and CYP3A23), after 5 to 6 day treatments with either DHEA, or nafenopin, a known peroxisome proliferator. Acyl-CoA oxidase and CYP4A1 were induced nearly identically by DHEA and nafenopin, with induction being more pronounced in female rats. However, CYP3A23 was induced only by DHEA, suggesting an induction mechanism independent of the peroxisome proliferator activated receptor. Previously, we observed triiodothyronine (T3) suppression of peroxisome proliferator induced CYP4As and we sought to determine whether CYP3A23 might be regulated in a different manner. T3 was found to also suppress DHEA-dependent induction of CYP3A23. CYP4A2 expression in kidney was also negatively regulated by T3. To characterize a putative negative thyroid hormone response element (nTRE) in the 5' flanking region of this gene, a luciferase reporter gene containing a rat CYP4A2 flanking sequence extending to -1865 bp was transfected into HepG2 cells along with human thryroid hormone receptor expression vector. Expression of luciferase activity was unaffected by T3, suggesting the absence of a functional nTRE within this portion of CYP4A2. These data demonstrate gene regulatory activity by DHEA different from that of nafenopin, and a suppressive effect of T3, consistent with indirect regulatory mechanisms not involving an nTRE.  PMID: 9929502 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9929502&dopt=Abstract

Metabolism of DHEA by cytochromes P450 in rat and human liver microsomal fractions.

Fitzpatrick JL, Ripp SL, Smith NB, Pierce WM Jr, Prough RA.  Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA.

Administration of dehydroepiandrosterone (DHEA) to rodents produces many unique biological responses, some of which may be due to metabolism of DHEA to more biologically active products. In the current study, DHEA metabolism was studied using human and rat liver microsomal fractions. In both species, DHEA was extensively metabolized to multiple products; formation of these products was potently inhibited in both species by miconazole, demonstrating a principal role for cytochrome P450. In the rat, use of P450 form-selective inhibitors suggested the participation of P4501A and 3A forms in DHEA metabolism. Human liver samples displayed interindividual differences in that one of five subjects metabolized DHEA to a much greater extent than the others. This difference correlated with the level of P4503A activity present in the human liver samples. For one subject, troleandomycin inhibited hepatic microsomal metabolism of DHEA by 78%, compared to 81% inhibition by miconazole, suggesting the importance of P4503A in these reactions. Form-selective inhibitors of P4502D6 and P4502E1 had a modest inhibitory effect, suggesting that these forms may also contribute to metabolism of DHEA in humans. Metabolites identified by LC-MS in both species included 16alpha-hydroxy-DHEA, 7alpha-hydroxy-DHEA, and 7-oxo-DHEA. While 16alpha-hydroxy-DHEA appeared to be the major metabolite produced in rat, the major metabolite produced in humans was a mono-hydroxylated DHEA species, whose position of hydroxylation is unknown. Copyright 2001 Academic Press.  PMID: 11339818 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11339818&dopt=Abstract

Our laboratory is also studying the effect of dehydroepiandrosterone on regulation of the cytochromes P450; DHEA is a peroxisome proliferator, but may have effects on enzyme systems in addition to those regulated by the peroxisome proliferator activated receptor (PPAR). Studies on rat 3A23 suggest that DHEA or a metabolite apparently regulate this gene, most likely through the action of the pregnane X receptor. DHEA is extensively metabolized by cytochromes P450 and hydroxysteroid dehydrogenases and their role in activation of PPAR, PXR and other members of subfamily III of the steroid hormone receptors are under study. New research areas have been initiated to evaluate the role of aging on expression on the enzymes of foreign compound metabolism in a rodent model, in conjunction with Eugenia Wang at UofL.

D J Waxman
Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215, USA
(Requests for offprints should be addressed to Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA)

Abstract
 The adrenal steroid dehydroepiandrosterone (DHEA) stimulates a dramatic increase in both the size, and the number, of peroxisomes present in liver when given to rodents at pharmacological doses.

Structurally diverse chemicals, including many fatty acids, hypolipidemic drugs and other foreign chemicals, can also induce such a peroxisome proliferative response. This response is associated with a dramatic induction of peroxisomal fatty acid ß-oxidation enzymes and microsomal cytochrome P450 4A fatty acid hydroxylases and, long-term, can lead to induction of hepatocellular carcinoma.

This review examines the underlying mechanisms by which DHEA induces peroxisome proliferation and evaluates the possible role of PPAR, peroxisome proliferator-activated receptor, in this process. Like DHEA, the 17&#223;-reduced metabolite 5-androstene- 3&#223;,17b-diol (ADIOL) is an active peroxisome proliferator when administered <i>in vivo, </i>whereas androgenic and estrogenic metabolites of DHEA are inactive. In primary rat hepatocytes, however, DHEA and ADIOL are inactive as inducers of P450 4A and peroxisomal enzymes unless first metabolized by steroid sulfotransferase to the 3&#223;-sulfates, DHEA-S and ADIOL-S. Investigations of whether DHEA utilizes the same induction mechanism employed by classic, foreign chemical peroxisome proliferators, namely, activation of the intracellular receptor molecule PPAR, have shown that DHEA-S and ADIOL-S are ineffective with respect to PPAR activation in transient transfection /<i>trans</i>-activation assays. This inactivity of DHEA-S <i>in vitro </i>suggests a requirement for specific cellular transport or for further metabolism of the steroid which is only met in liver cells. Alternatively, the action of DHEA-S may require accessory proteins or other nuclear factors that modulate the activity of PPAR, such as RXR, HNF-4 or Coup-TF. Investigations using Ca⁽⁺²⁾-channel blockers such as nicardipine suggest that there are important mechanistic similarities between the foreign chemical- and DHEA-S- stimulated induction responses, and support the hypothesis that these two classes of peroxisome proliferators both activate Ca⁽⁺²⁾-dependent signaling pathways.

Further studies are required to ascertain whether this potential of DHEA and its sulfated metabolites to serve as physiological modulators of fatty acid metabolism and peroxisome enzyme expression contributes to the striking anti-carcinogenic and other useful chemoprotective properties that DHEA is known to possess.

Steroid hydroxylation, catalyzed by cytochrome P450 (or CYP) enzymes, and steroid sulfation, catalyzed by steroid sulfotransferase enzymes, are two important metabolic pathways for dehydroepiandrosterone (DHEA) and related steroids (Fig. 1). This article reviews recent studies of these two pathways and their influence on the interaction of DHEA with CYP enzymes. First, the factors that govern the site-specific steroid hydroxylation reactions that P450 enzymes catalyze will be examined. Next, studies on the peroxisome proliferative properties of DHEA will be reviewed in the context of recent studies on PPAR, peroxisome proliferator- activated receptor. The associated stimulatory effect that DHEA has on the expression in liver and kidney of P450 4A fatty acid hydroxylases is discussed, and the importance of DHEA sulfation for this peroxisome proliferative response is highlighted. Finally, our current knowledge of the mechanisms underlying the peroxisome proliferative response induced by DHEA and other chemicals classified as peroxisome proliferators is evaluated with the goal of identifying important remaining questions for future investigation.

Journal of Endocrinology

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http://journals.endocrinology.org/joe/150/joe150s129.htm