Induction of a deficiency of steroid delta 4-5 alpha-reductase activity in liver by a porphyrinogenic drug.

Kappas, Attallah; Bradlow, H. Leon; Bickers, David R.; Alvares, Alvito P.

doi:10.1172/jci108614

Cited by 26 publications

(8 citation statements)

References 21 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.…”

supporting

confidence: 54%

“…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: 60%

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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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supporting

confidence: 54%

Section: Discussionmentioning

confidence: 60%

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.

Self Cite

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“…However, the effects of dietary protein on the mixed function oxidase system are similar in some respects to those of barbiturates and include an increase in hepatic content of cytochrome P-450 (22). Administration of phenobarbital or other inducing chemicals to rats stimulates the microsomal hydroxylase activities for a number of steroids (23)(24)(25), including estrogen 2-hydroxylase (14), and this treatment also stimulates the hydroxylation of certain steroids in humans (26), while decreasing the 5a-reductive metabolism of others (27). Steroid hormones, and their metabolites, in turn, may function as endogenous regulators of cytochrome P-450 (8,28,29), and steroid biotransformation products also have potent effects on other metabolic processes in hepatic and other cell types (26,27,(30)(31)(32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

The Influence of Dietary Protein and Carbohydrate on the Principal Oxidative Biotransformations of Estradiol in Normal Subjects*

Anderson¹,

Kappas

Conney

et al. 1984

The Journal of Clinical Endocrinology & Metabolism

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Dietary protein, when substituted for carbohydrate or fat, can increase cytochrome P-450-dependent drug oxidation rates in humans. Endogenous estrogens, as well as drugs, are also metabolized by cytochrome P-450 and other enzymes in the hepatic endoplasmic reticulum. Therefore, it was of interest to determine whether variations in diet can alter the major metabolic pathways for estrogens, as assessed by radiometric methods. Eight normal men were fed a high protein diet (44% of calories as protein, and 35% as carbohydrate for 2 weeks), followed by a high carbohydrate diet (70% of calories as carbohydrate and 10% as protein) for an additional 2 weeks. The fat and total energy contents of the two diets were equal. The percent oxidation of [2-3H]estradiol, measured as 3H2O released, which is an in vivo measure of 2-hydroxylation of endogenous estrogen, was greater in all eight men during the high protein dietary period than during the high carbohydrate dietary period (44 +/- 3% and 33 +/- 3%, respectively, means +/- SE, P less than 0.005). In contrast, 16 alpha-hydroxylation of estrogen, as measured using [16 alpha-3H]estradiol, did not change significantly. Our findings demonstrate that dietary components can alter estradiol oxidation in humans and that the 2- and 16 alpha-hydroxylases for estrogen are under separate regulatory control. The influences of specific nutrients on estrogen metabolism may have potential significance for diseases in which these hormones may play a role in clinical expression.

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“…findings, e.g., Cushing syndrome (31 ), hypothyroidism (32 ), anorexia nervosa (33 ), and consumption of some drugs (34 ). The ratios in these patients are seldom as extreme as in 5ARD.…”

Section: Diagnosis Of 5␣-reductase 2 Deficiencymentioning

confidence: 99%

Diagnosis of 5α-Reductase 2 Deficiency: Is Measurement of Dihydrotestosterone Essential?

Chan¹,

But²,

Lee³

et al. 2013

Clinical Chemistry

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BACKGROUND 5α-Reductase 2 deficiency (5ARD) is a known cause of 46,XY disorders of sex development (DSD). Traditionally, the diagnosis relies on dihydrotestosterone (DHT) measurement, but the results are often equivocal, potentially leading to misdiagnosis. We reviewed alternative approaches for diagnosis of 5ARD. METHODS We conducted a retrospective review of the results of urinary steroid profiling (USP) by GC-MS and mutational analysis of SRD5A2 [steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2)] by PCR and direct DNA sequencing of all 46,XY DSD patients referred to our laboratory with biochemical and/or genetic findings compatible with 5ARD. We also performed a literature review on the laboratory findings of all 5ARD cases reported in the past 10 years. RESULTS Of 16 patients diagnosed with 5ARD between January 2003 and July 2012, 15 underwent USP, and all showed characteristically low 5α- to 5β-reduced steroid metabolite ratios. Four patients had DHT measured, but 2 did not reach the diagnostic cutoff. In all 12 patients who underwent genetic analysis, 2 mutations of the SRD5A2 gene were detected to confirm the diagnosis. Twenty-four publications involving 149 patients with 5ARD were published in the review period. Fewer than half of these patients had DHT tested. Nearly 95% of them had the diagnosis confirmed genetically. CONCLUSIONS 5ARD can be confidently diagnosed by USP at 3 months postnatally and confirmed by mutational analysis of SRD5A2. Interpretation of DHT results may be problematic and is not essential in the diagnosis of 5ARD. We propose new diagnostic algorithms for 46,XY DSD.

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Induction of a deficiency of steroid delta 4-5 alpha-reductase activity in liver by a porphyrinogenic drug.

Cited by 26 publications

References 21 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.

The Influence of Dietary Protein and Carbohydrate on the Principal Oxidative Biotransformations of Estradiol in Normal Subjects*

Diagnosis of 5α-Reductase 2 Deficiency: Is Measurement of Dihydrotestosterone Essential?

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