Synthesis and metabolism of vertebrate-type steroids by tissues of insects: a critical evaluation

This review covers the synthesis and the metabolism of vertebrate-type steroids (progesterone, testosterone, estradiol, corticosteroids) by insect tissues and discusses the significance of the reactions for insect physiology. Biosynthesis of vertebrate-type steroids from cholesterol hitherto has been demonstrated in only two insect species, i.e. the water beetle Acilius sulcatus (Coleoptera) and the tobacco hornworm Manduca sexta (Lepidoptera). In Acilius, steroid synthesis is associated with exosecretion (chemical defense). Nothing, however, is known about a physiological role of the C21 steroid conjugate present in ovaries and eggs of Manduca. No synthesis of vertebrate-type steroids was observed in any other insect investigated to date. Most metabolic conversions of steroids by insects concerned oxidoreduction of oxygen groups (hydroxysteroid dehydrogenase activity) and (polar and apolar) conjugate formation. All important enzymatic steps involved in synthesis and catabolism, as known from studies with tissues of vertebrates, were not, or hardly observed. The conclusion is drawn that typical vertebrate-type (C21, C19 and C18) steroids probably do not act as physiologically active substances in insects.     

Adenine nucleotide metabolism during anoxia and postanoxic recovery in insects

Severe hypoxia (anoxia), if maintained for more than a few minutes, causes irreversible damage in humans and other mammals. Why mammals are so vulnerable to anoxia is not fully understood. It is therefore of interest to study animals that are more tolerant of anoxia in order to identify physiological and metabolic properties that are correlated with a high tolerance of anoxia. Insects have high metabolic rates and their energy metabolism is dependent on aerobic ATP production. In insects, as in mammals, anoxia causes a rapid breakdown of physiological function, resulting in a state similar to rigor mortis. This is accompanied by a precipitous decrease in metabolic rate. In contrast to mammals, however, insects can survive anoxia for many hours and recover spontaneously and completely when air is again available. We have followed the metabolism of adenine nucleotides in locust tissues (mainly in the flight muscle) over 3 h of anoxia and during recovery from 1 h of anoxia. The content of ATP in the flight muscle dropped to 1% of normal during 2 h of anoxia. The main product was AMP which increased in content more than 20-fold. Some of the AMP was deaminated to IMP and this was further dephosphorylated to inosine. Altogether less than 30% of the total adenine nucleotides were degraded during 3 h of anoxia and this may contribute to the amazing ability of insects to recover from prolonged anoxia.     

Uterine glucose metabolism in the prepubertal rat treated neonatally with androgen,estrogen, and antihormones

Summary Estrogen secretion during infancy may selectively enhance the phosphogluconate oxidative pathway in the rat uterus, for altered estrogen-stimulated glucose oxidation prepubertally is correlated (+0.91) with impaired ovarian development and not uterine estrogen receptor content.This work was supported in part by NSF Research Grant PCM-8409586.     

A comparison of cycloartenol and lanosterol biosynthesis and metabolism by the Oomycetes

Summary Representative members in each of the four orders of Oomycetes (Phytophthora cactorum, Peronosporales;Lagenidium callinectes, L. giganteum, Lagenidiales;Saprolegnia ferax, Saprolegniales;Apodachylella completa, Leptomitales) have been examined for their ability to synthesize and polycyclize squalene-oxide (SO) to a tetracyclic product and to differentiate between cycloartenol and lanosterol metabolism to sterols.P. cactorum andL. giganteum failed to synthesize or metabolize SO, cycloartenol or lanosterol. While the other three fungi synthesized sterols via SO and lanosterol, a minor metabolism of added cycloartenol to the 4,4-desmethyl-14-methylcyclosteroid dehydropollinastanol was observed.Acknowledgment.Saprolegnia ferax-ATCC 3605 (1),Lagenidium callinectes ATCC 24973 (2),Apodachlyella completa (3) were obtained from Dr J. Aronson, Arizona State Univ. (3),Lagenidium gigateum was obtained from a drainage ditch in California (4), andPhytophthora cactorum was obtained from the U.C. Berkeley Fungal Collection (5). The fungi were cultured as previously described: Cultures 1,2,3: Berg, L. B., Ph. D. dissertation, Univ. of MD., College Park (1983); culture 4: Kerwin, J.L., and Washino, R.K., Exp. Mycol.7 (1983) 109; culture 5: Nes, W.D., and Stafford, A.E., Lipids19 (1984) 544. Preliminary observations involving the labeled substrates were presented by Le, P.H., Nes, W.D., and Parish, E.J. J. Am. Oil Chem. Soc.62 (1985) 655(A). Please address all correspondence to W.D. Nes, Plant Physiology and Chemistry Research Unit, ARS-US Dept of Agriculture, Berkeley, CA 94710, USA.     

Estimation of serotonin and its action on oviducts and uteri of some oviparous and viviparous insects

Summary Serotonin was not found in the oviducts ofBlabera gigantea, Clitumnus extradentatus nor in the uterus ofGlossina, but it is present in the uterus ofBlabera. It is also found in the central nervous system of all three insects. In vitro experiments confirm these data by showing that serotonin increases the contractions of the uterus ofBlabera, but has no effect on the uterus ofGlossina.     

In vitro metabolism of the trichothecene 4-monoacetoxyscirpenol by fungus- and non-fungus-feeding insects

Summary The metabolism of the trichothecene 4-monoacetoxyscirpenol by intact gut tissue was determined in the fungus-feeding Nitidulid,Carpophilus hemipterus (L.) and the non-fungus-feeding caterpillars, the fall armyworm,Spodoptera frugiperda (J. E. Smith) and the corn earworm,Heliothis zea (Boddie). The primary metabolite was the hydrolysis product scirpentriol. The amount of metabolism by theC. hemipterus larvae was ca 10 times that of the caterpillars on a per mg protein basis, suggesting metabolic adaptation for feeding on fungi that may contain mycotoxins.Acknowledgment. The authors wish to thank S. Taylor for technical assistance.The mention of firm names or trade products does not imply that they are endorsed or recommended by the U.S. Department of Agriculture over other firms or similar products not mentioned.     

Familial hypobetalipoproteinemia: genetics and metabolism

Familial hypobetalipoproteinemia (FHBL), an autosomal dominant disorder, is defined as <5^th percentile LDL-cholesterol or apolipoprotein (apo) B in the plasma. FHBL subjects are generally heterozygous and asymptomatic. Three genetic forms exist: (i) premature stop codon specifying mutations of APOB; (ii) FHBL linked to a susceptibility locus on the chromosome 3p21; and (iii) FHBL linked neither to APOB nor to the chromosome 3p21. In heterozygous apoB-defective FHBL, the hepatic VLDL export system is defective because apoB 100, the product of the normal allele, is produced at ∼25% of normal rate, and truncated apoB is cleared too rapidly. The reduced capacity for hepatic triglyceride export increases hepatic fat three-fold. Indexes of adiposity and insulin action are similar to controls. ‘Knock-in’ mouse models of apoB truncations resemble human FHBL phenotypes. Liver fat in the chromosome 3p21-linked FHBL is normal. Elucidation of the genetic basis of the non-apoB FHBL could uncover attractive targets for lipid-lowering therapy. (See note added in proof.)Received 27 October 2004; received after revision 1 February 2005; accepted 22 February 2005     

Comparison of lysine and tryptophan catabolizing enzymes in rat and bovine tissues

Summary Earlier studies indicate that -aminoadipate aminotransferase (AadAT) and kynurenine aminotransferase (KAT) activities from rat tissues are associated with a single protein. However, our recent studies indicate that AadAT activity from bovine liver and kidney is not associated with KAT activity. To test whether the lysine and tryptophan catabolism in bovine tissues differ from that in rat tissues, we compared the activities of enzymes involved in lysine and tryptophan pathways in rat and bovine tissues. The activities of lysine catabolizing enzymes such as AadAT, lysine -ketoglutarate reductase and saccharopine dehydrogenase in the bovine tissues were significantly lower than those found in rat tissues. The activities of tryptophan catabolizing enzymes such as KAT and kynurenine hydroxylase in the bovine tissues were negligible as compared to those in rat tissues. The results suggest that lysine is degraded via the saccharopine pathway in the livers and kidneys of both species but the metabolism of tryptophan in bovine tissues may be different from that in rat tissues.Acknowledgments. This work was supported by a grant from the Children's Hospital of Michigan and by a Research Career Development Award from the National Institutes of Health to D. R. Deshmukh.     

Cytochromes P450 and metabolism of xenobiotics

Cytochromes P450 (henceforth P450s) are involved in a variety of metabolic and biosynthetic processes. The number of known P450 enzymes exceeds 1000, while the endogenous substrates of most of them remain unknown. All P450 enzymes exhibit similarity in their structure and general mechanism of action; however, there are significant differences in the detailed function of individual enzymes as well as in the structures and properties of their active sites. This review discusses the properties of the most important P450 enzymes taking part in drug metabolism in humans. P450 3A4 is of paramount importance, because it is the most abundant P450 in the human liver and is known to metabolize the majority of drugs whose biotransformation is known. Genetically dependent variabilities of individual P450 activities and levels are described, documenting the importance of pharmacogenetics aimed at explaining differences in the response of the organism to various drugs. Received 7 November 2000; received after revision 9 January 2001; accepted 10 January 2001     

Genetic factors in neurotoxicology and neuropharmacology: A critical evaluation of the use of genetics as a research tool

Animals have evolved a detoxication system to enable them to survive in a hostile chemical environment in which foods contain many non-nutrient chemicals. Detoxication depends on enzymes which are often genetically polymorphic. As a result, inter-individual variation is common, and in humans several Mendelian loci have been identified. However, most variation in response is probably due to the action of several genes. Genetic variation in response to the neurotoxin MPTP and to chemically and physically-induced seizures is reviewed. In the former case, differences between pigmented and white mouse strains have been noted which are consistent with the hypothesis that humans are more sensitive than mice or rats because of the presence of melanin in human brains. However, variation in sensitivity probably also depends on other genes. In the case of audiogenic seizures, a single locus has been identified and mapped, but its relationship with seizures induced by other agents is not clear. Genetic variation in response to alcohol is also discussed. The failure of most toxicologists to consider genetic variation as a potentially confounding variable, and as a powerful research tool, is discussed critically in relation to non-repeatability of research on the neurotoxic effects of lead, and in relation to the genetic variation in MPTP, seizures, and alcohol response already noted. It seems clear that genetic methods provide a powerful research tool which is largely being ignored by toxicologists.     

Magnetic resonance and the human brain: anatomy, function and metabolism

The introduction and development, over the last three decades, of magnetic resonance (MR) imaging and MR spectroscopy technology for in vivo studies of the human brain represents a truly remarkable achievement, with enormous scientific and clinical ramifications. These effectively non-invasive techniques allow for studies of the anatomy, the function and the metabolism of the living human brain. They have allowed for new understandings of how the healthy brain works and have provided insights into the mechanisms underlying multiple disease processes which affect the brain. Different MR techniques have been developed for studying anatomy, function and metabolism. The primary focus of this review is to describe these different methodologies and to briefly review how they are being employed to more fully appreciate the intricacies associated with the organ, which most distinctly differentiates the human species from the other animal forms on earth. Received 1 November 2005; received after revision 11 January 2006; accepted 25 January 2006     

Allergic encephalomyelitis: Inhibition of cellular passive transfer by exogenous and endogenous steroids

Zusammenfassung Injektionen des Antientzündungssteroids Dexamethasone oder eine Hypersekretion des endogenen Kortikosteroids als eine Reaktion zum unspezifischen Stress verhindern die zelluläre passive Übertragung allergischer Enzephalomyelitis. Deshalb kann angenommen werden, dass Steroide die enzephalitogene Wirkung von vollkommen immunisierten Lymphoidzellen verhindern.

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Supported by National Multiple Sclerosis Society grant No. 536A10 and United States Public Health Service grant No. HD 02261-03. R.Sowinski and B. H.Brown assisted in the experiments. Dr. H. B.Devlin, Parke Davis & Co., Detroit, kindly supplied the pertussis vaccine.     

Influence of phenobarbital and TCDD on the hepatic metabolism of TCDD in the dog

Summary The influence of phenobarbital and TCDD pretreatment on the formation and biliary excretion of TCDD-metabolites following single doses of³H-TCDD was investigated. Without pretreatment, 24.5% of the absorbed³H-TCDD dose was excreted in the bile within 110 h. Phenobarbital did not influence this rate, whereas a single dose of 10 g of unlabeled TCDD/kg b.wt nine days earlier resulted in a doubling of the amount of radioactive material eliminated in the bile (47.4%).     

Juvenile hormones inThermobia domestica females: Identification and quantification during biological cycles and after precocene application

Summary JH I and JH III immunoreactive substances were detected in the hemolymph of imaginal females of the primitive insectThermobia domestica. Periodic changes in the levels of these hormones were investigated in correlation with molting and reproductive cycles in inseminated, virgin and precocene-treated females. The presumed influence of JH III on the various phases of vitellogenesis is discussed, also taking into account the periodic changes of the hemolymphatic ecdysteroid levels.     

Steroid hormones and the cardiovascular system: Direct actions of estradiol,progesterone, testosterone,gluco- and mineralcorticoids,and soltriol [vitamin D] on central nervous regulatory and peripheral tissues

Summary Knowledge of steroid hormone sites of action and related effects in cardiovascular and neural regulatory tissues is reviewed. Evidence for nuclear receptor sites is derived mainly from autoradiographic studies with relatively intact tissues and some biochemical studies with tissue homogenates.In the heart and in the walls of blood vessels, estradiol, dihydrotestosterone, corticosterone, aldosterone, dexamethasone, and soltriol (vitamin D) show nuclear binding. In the brain and spinal cord, neuronal regions associated with cardiovascular regulation contain nuclear receptors in specific patterns for each steroid hormones, including progesterone and soltriol. These data indicate that all steroid hormones exert direct actions on the cardiovascular system at its different levels of organization, thus enabling adjustment to the changing demands during reproduction (gonadal steroids), stress (adrenal steroids), and solar seasons (vitamin D-soltriol).     

The effect of castration,testosterone and estradiol on14C-serotonin metabolism by organ cultures of male rat pineal glands

Summary The pineal gland of the male rat does not appear to rely on prior conversion of testosterone to estradiol for the stimulant effect of testosterone on pineal melatonin and 5-methoxytryptophol synthesis.     

Neuroactive steroids: State of the art and new perspectives

Neuroactive steroids include synthetic steroidal compounds and endogenous steroids, produced by endocrine glands (hormonal steroids) or the nervous tissue (neurosteroids), which regulate neural functions. These steroids bind to nuclear receptors or act through the activation of membrane-associated signaling pathways to modulate various important processes including the development of the nervous system, neural plasticity and the adaptive responses of neurons and glial cells under pathological conditions. Reviewed and updated in the present paper are the pleiotropic and protective abilities of neuroactive steroids. The fundamental evidence and knowledge gained constitute a profound background that offers interesting possibilities for developing effective strategies against several disorders of the nervous system. Received 3 September 2007; received after revision 24 October 2007; accepted 29 October 2007