Influence of pregnenolone-16α-carbonitrile on the anesthetic effect and hepatic microsomal metabolism of progesterone in the rat

Zsigmond, G.; Solymoss, B.

doi:10.1016/0006-2952(72)90328-0

Cited by 8 publications

(11 citation statements)

References 13 publications

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“…The changes in the 5a-reductive metabolism of testosterone and in the cytochrome P-450-dependent steroid and drug oxidations produced by diet resemble those previously shown to result from phenobarbital administration in humans (15) or from certain environmental chemical exposures in animals (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). Thus, the protein/carbohydrate ratio of the human diet significantly alters the patterns of metabolism of natural steroid hormones, and these alterations can mimic those produced by exogenous chemicals.…”

mentioning

confidence: 65%

“…Both metabolic systems examined in this study (i.e., cytochrome P-450-dependent oxidation and A4-5a-steroid reduction) are localized in endoplasmic reticulum membranes in the liver, but they appear to be regulated in a reciprocal fashion in certain circumstances. This reciprocal relationship extends beyond the dietary effects examined in this study because, as summarized in Table 2, a decrease in hepatic M4-5a-steroid reductive activity also has been identified in animals or in humans at a time when enhanced activity or induction of the cytochrome P-450 system by drugs or environmental chemicals has been produced (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). The agents that have been shown to elicit these dual effects on cytochrome P-450-dependent oxidations and the A4-5a-reductive metabolism of steroids include phenobarbital, hexachlorobenzene, dioxin, dibenzofurans, and polyhalogenated biphenyls.…”

Section: Discussionmentioning

confidence: 99%

“…Eight normal male volunteers (ages [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] yr, weights 54-95 kg) were studied. All were nonsmokers, ingested no drugs other than occasional aspirin, and were normal by history, physical examination, and common clinical laboratory tests.…”

Section: Methodsmentioning

confidence: 99%

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Nutrition-endocrine interactions: induction of reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-dependent oxidation of estradiol by dietary macronutrients in man.

Kappas¹,

Anderson²,

Conney³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

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The in vivo biotransformations of drugs known to be metabolized by enzymes localized in the endoplasmic reticulum of liver can be greatly altered by diet in humans, as we have shown previously. Steroid hormones also are metabolized extensively by hepatic microsomal enzymes; therefore, we examined the possibility that testosterone and estradiol biotransformations, as assessed with radiolabeled tracer methods, could be influenced by dietary macronutrients. Normal males were fed a high-protein diet for 2 weeks, followed by a high-carbohydrate diet for an additional 2 weeks. The A4-5a-reduction of testosterone was considerably diminished, while the cytochrome P-450-dependent hydroxylation of estradiol at the C2 position was substantially enhanced during ingestion of the high-protein diet as compared with the high-carbohydrate diet. These results indicate that dietary macronutrients can significantly alter major metabolic pathways for testosterone and estradiol in man. The mechanism by which reciprocal changes in the A4-5a-reduction of testosterone and the cytochrome P-450-mediated oxidation of estradiol are produced by diet is not known. Similar changes in steroid A4-5a-reduction and cytochrome P-450-dependent chemical oxidations have been observed in circumstances in which the mixed-function oxidase system in liver is induced by agents such as phenobarbital, hexachlorobenzene, dioxin, and polyhalogenated biphenyls. Thus, the alterations in steroid hormone metabolism produced by dietary macronutrients in man mimic those that can be produced by drugs and environmental chemicals.The oxidative metabolism of drugs can be greatly influenced by specific components of the human diet, as studies from our laboratories have shown (1-8). These studies demonstrated that feeding humans cruciferous vegetables (5), charcoal-broiled beef (6-8), or a high-protein/low-carbohydrate diet (1-4) stimulates the metabolism of certain drugs by the microsomal cytochrome P-450-dependent mixed-function oxidase system. Natural steroid hormones, like many drugs and other foreign chemicals, also undergo biotransformations mediated by microsomal enzymes (9-12); therefore, it was of interest to determine whether the dietary content of protein and carbohydrate could alter the metabolism of such hormones in humans. The major sex steroids, testosterone and estradiol, were chosen for study because cytochrome P-450-dependent oxidation is the principal metabolic fate of the latter compound (12, 13), whereas reduction by a microsomal A4-5a-reductase represents a primary biotransformation for the androgen (14). Thus by changing, in a carefully controlled fashion, the dietary intakes of protein and carbohydrate in the same individuals, the role of specific nutritional factors in determining the metabolic fate of these steroid hormone substrates of microsomal enzymes could be determined. The metabolism of antipyrine also was studied because the effects of protein and carbohydrate in the diet on the oxidative disposition of this cytochrome P-450 subs...

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mentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

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Nutrition-endocrine interactions: induction of reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-dependent oxidation of estradiol by dietary macronutrients in man.

Kappas¹,

Anderson²,

Conney³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…These two steroids augment hepatic weight, cause smooth-surfaced endoplasmic reticulum proliferation in hepatocytes (6,7), and induce mixed-function oxygenases (8,9) and UDP-glucuronyl transferases in liver microsomes (2,3) as well as glutathione-S-aryl-transferases in the cytosol of rats (4). The above changes could explain many of the protective actions of spironolactone and PCN.…”

mentioning

confidence: 92%

“…In rats, spironolactone and pregnenolone-1 6~carbonitrile (PCN) increase resistance to many intoxications (1) and accelerate the biotransformation and elimination of several substrates (2)(3)(4)(5). These two steroids augment hepatic weight, cause smooth-surfaced endoplasmic reticulum proliferation in hepatocytes (6,7), and induce mixed-function oxygenases (8,9) and UDP-glucuronyl transferases in liver microsomes (2,3) as well as glutathione-S-aryl-transferases in the cytosol of rats (4).…”

mentioning

confidence: 98%

Increased Canalicular Bile Production Induced by Pregnenolone-16 -Carbonitrile, Spironolactone and Cortisol in Rats

Zsigmond

Solymoss

1974

Experimental Biology and Medicine

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Effect of 16α-cyanopregnenolone on the hydroxylation of lithocholic acid by rat liver microsomes

Einarsson

Gustafsson

1974

Biochemical Pharmacology

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Influence of pregnenolone-16α-carbonitrile on the anesthetic effect and hepatic microsomal metabolism of progesterone in the rat

Cited by 8 publications

References 13 publications

Nutrition-endocrine interactions: induction of reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-dependent oxidation of estradiol by dietary macronutrients in man.

Nutrition-endocrine interactions: induction of reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-dependent oxidation of estradiol by dietary macronutrients in man.

Increased Canalicular Bile Production Induced by Pregnenolone-16 -Carbonitrile, Spironolactone and Cortisol in Rats

Effect of 16α-cyanopregnenolone on the hydroxylation of lithocholic acid by rat liver microsomes

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