The steroid 16α-hydroxylase system in mammalian liver

Heinrichs, Wm. LeRoy; Feder, Harvey H.; Colás, A.E.

doi:10.1016/0039-128x(66)90137-1

Cited by 58 publications

(16 citation statements)

References 11 publications

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“…Because of the reports of sex differences in the rate of metabolism of certain drugs in experimental animals (18)(19)(20), the data from the control studies were analyzed according to sex (14 males and 4 females). No significant differences in the pattern of distribution of urinary metabolites, the amounts of drug recovered during the investigations, or the apparent half-lives of metabolite excretion were noted between the two sexes.…”

Section: Introductionmentioning

confidence: 99%

The influence of pyrogen-induced fever on salicylamide metabolism in man

Cao¹,

Gelb²,

Wolff³

1972

J. Clin. Invest.

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A B S T R A C T Salicylamide is metabolized in man by biotransformation to salicylalmide glucuronide, salicylamide sulfate, and gentisamide glucuronide. The metabolites are quantitatively and rapidly excreted in urine. Study of the metabolism of this drug in volunteers during episodes of pyrogen-induced fever shows a significant reduction in the half-life (ti) of the excretion of the drug metabolites. The proportion of the drug transformed to its major metabolite, salicylamide glucuronide, is significantly reduced by fever, with concomitant increase in the proportion of one or both of the other metabolites. Thus, the pattern of urinary metabolites of salicylamide is altered. The shortened ti of the metabolite excretion is probably due to increased hepatic and renal blood flow known to accompany pyrogen-induced fever. This concept was supported by the observation that when two subjects were placed in a high-temperature environmental chamber, a condition in which hepatic and renal blood flows are known to diminish, the ti of salicylamide metabolite excretion actually increased. No simple explanation exists to explain the changed metabolite pattern noted during febrile periods. It is most likely to be due to complex interactions between the direct or indirect effects of the pyrogens and the factors affecting the hepatic biotransformation of drugs. INTRODUCTIONDespite the widespread use of pharmacological agents such as analgesics, antipyretics, antibiotics, and antimetabolites in diseases associated with fever, little is known of the effect of fever on the disposal of drugs in man. We have studied the metabolism of salicylamide in normal volunteers before and after induction of artificial fever by administration of etiocholanolone or endotoxin (1-3). Salicylamide (o-hydroxybenzamide) is an amide

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Section: Introductionmentioning

confidence: 99%

The influence of pyrogen-induced fever on salicylamide metabolism in man

Cao¹,

Gelb²,

Wolff³

1972

J. Clin. Invest.

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“…The extensive 16a-hydroxylation of 3a-hydroxy5a(and 5B)-androstan-17-one described by Heinrichs et al [30] and the lack of 16a-hydroxylation of 5a-androstane-3a(and 3j3),17~-diols found by us, can only be explained by a different metabolism of 17-0x0-and 17~-hydroxy-C,,-steroids ("17-0x0 and 178-hydroxy pathways'' [32]). Experiments are in progress to investigate the significance of the 17-0x0 pathway in the formation of polar C,,O, metabolites of testosterone.…”

Section: Discussionmentioning

confidence: 91%

“…Both testosterone and its saturated derivatives are hydroxylated, the latter compounds sometimes to a greater extent than testosterone. Heinrichs et al [30] found that the activity of the 16a-hydroxylase of lyopliilized rat liver microsomes was higher for the 3-hydroxy-5a( and 5p)-androstan-l 7-one epimers than for androst-4-ene-3J7-dione and testosterone. These results are in accordance with those of Chamberlain et al [31] who found that saturated C,,-steroids are better substrates for hydroxylation than their 3-0x0-Ad-analogues.…”

Section: Discussionmentioning

confidence: 98%

Studies on the Metabolism of C₁₉‐Steroids in Rat Liver

Gustafsson

Lisboa

Sjöval

1968

European Journal of Biochemistry

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The formation of androstanetriols after incubation of testosterone with 105,000 x g microsomes of adult male rat liver was investigated. The steroids were isolated by thin-layer chromatography and were identified by gas chromatography-mass spectrometry as 5 a-androstane2p,3a,l7p-triol, 5u-androstane-3a,7a,l7,!?-triol and 5a-androstane-3a(and 3/?),16~,17p-triol. Incubation of 2p-and 7a-hydroxytestosterone only gave androstanetriols with a 3a-configuration while incubation with 6,9-and 16a-hydroxytestosterone resulted in the formation of both the 3a-and 3B-epimers of the respective androstanetriols. After incubation with Ba-dihydrotestosterone the following androstanetriols were isolated : 5a-androstane-2/?,3a(and 3p),17p-triol, 5a-androstane-3a(and 3,!?),7a,17/3-triol and 5a-androstane-3a(and 3,3),16a,17~-triol. No steroid with a 6p-hydroxy group could be isolated after this incubation. When 5a-androstane-3a,17,4-diol was incubated only 5a-androstane-2fl,3a,l7p-triol was formed, and 5cc-androstane-3p,l7p-diol was not hydroxylated in the microsomes. These findings indicate a substrate specificity for the 2p-, 6g-, 7a-and 16a-hydroxylases.After incubation of testosterone with 105,000 x g liver microsomes from male germfree rats the same metabolites were isolated as after incubation with microsomes from conventional rats.Several studies have shown that saturated C,,O, steroids are formed during the metabolism of testosterone in rat liver. These polar metabolites have been detected after incubation of mince [l] and microsome preparations [2--41 as well as after liver perfusion [5] with testosterone.

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“…Heinrichs et al [26] have investigated the 16a-hydroxylating activity of lyophilized rat liver microsomes on several C,, and C,, steroids ; they have found that the 16a-hydroxylating system is active for several 17-ketosteroids, but that a 17/3-hydroxy group might exert a negative influence on the rate of 16a-hydroxylation, Among the 17i9-hydroxysteroids investigated were testosterone and estradiol but not 5a-dihydrotestosterone. The present study has demonstrated that 16a-hydroxytestosterone is further metabolized in rat liver microsomes to form 16a-hydroxy-5a-dihydrotestosterone and that the latter compound can serve as substrate for a 16a-hydroxylase in rat liver.…”

Section: Discussionmentioning

confidence: 99%

Studies on the Metabolism of C₁₉ Steroids in Rat Liver

Gustafsson

Lisboa²,

Sjövall

1968

European Journal of Biochemistry

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The formation of polar, saturated C,,steroids with a 3-keto-5a-configuration after incubation of 17~-hydroxyandrost-4-en-3-one (testosterone) with 105,000 x g microsomes of adult male rat liver was investigated. The metabolites were isolated by thin-layer chromatography and were identified as 2,5-,6/3-(tentatively), 7a-, and 16a-hydroxy-5a-dihydrotestosterone by means of gas chromatography-mass spectrometry. The same compounds were also isolated after incubation with 2P-,6,B-,7n-, and 16a-hydroxytestosterone, respectively. Incubation with 5a-dihydrotestosterone, however, resulted in the formation of 2P-,7a-, and 1661-hydroxy-5a-dihydrotestosterone whereas no 6p-hydroxy-5a-dihydrotestosterone could be found.After incubation of [f4C]-testosterone with rat liver microsomes the formation of reduced products reaches a maximum in only 2 to 4 minutes, whereas the amount of hydroxylated products continues to increase during the incubation [l]. These findingsin both female and male rats-indicate that the 5a-reduced derivatives of testosterone are further metabolized in rat liver microsomes.In our previous investigation on the hydroxylation of testosterone in rat liver microsomes, a number of saturated polar metabolites were also observed [2]. The isolation and identification of four of these saturated compounds, 2P-hydroxy-5cc-dihydrotestosterone, 6P-hydroxy-5cx-dihydrotestosterone, 7 cchydroxy-5cr-dihydrotestosterone and 16~-hydroxy5cc-dihydrotestosterone will be described in this paper. MATERIALSThe sources of the reagents and solvents used in this investigation were the same as described in a previous paper [2].Animals. Male Sprague-Dawley rats were used in all experiments. The 200 to 300 g animals were Enzymes. Isocitrate dehydrogenase (NADPH), threo-Dsisocitrate: NADP oxido-reductase (EC 1.1.1.42); 4,5a: A4-oxidoreductase and 4,5,3:A4-oxidoreductase (EC 1.3.1.) ; steroid hydroxylases (EC 1.14.1).Note. Trivial names used are defined as follows: Testosterone, 17B-hydroxyandrost-4-en-3-one; androstenedione, androst-4-ene-3,17-dione; androstanedione, 5a-androstane-3,17-dione; 5~-dihydrotestosterone, 17,3-hydroxy-5a-androstan-3-one; dehydroepiandrosterone, 3B-hydroxyandrost-5-en- 17-one; progesterone, pregn-4-ene-3,20-dione; estradiol, estra-l,3,5( lO)-triene-3,17,3-diol. Steroids. Testosterone and 5 cc-dihydrotestosterone were purchased from Schering A.G. (Berlin, Germany); the other steroids were kindly supplied by Dr. K. Irmscher (7cc-hydroxytestosterone), Dr. R. Neher (16a-hydroxytestosterone), Dr. N. Rao (2P-hydroxytestosterone, 2/3-and 2a-hydroxyprogesterone), Dr. L. Reineke (6P-hydroxytestosterone and 15a-hydroxytestosterone), Dr. W. J. A. VandenHeuvel (16cc-hydroxy-5cc-dihydrotestosterone), and Dr. M. 3 a,38,. All the steroids used in the incubations were assayed for purity by thin-layer and gas-liquid chromatography. EXPERIMENTAL METHODSThin-Layer Chromatography. Single or multiple one-dimensional thin-layer chromatography was carried out as described before [3,4] using both preparative (1 mm thick, No. 571...

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The steroid 16α-hydroxylase system in mammalian liver

Cited by 58 publications

References 11 publications

The influence of pyrogen-induced fever on salicylamide metabolism in man

The influence of pyrogen-induced fever on salicylamide metabolism in man

Studies on the Metabolism of C₁₉‐Steroids in Rat Liver

Studies on the Metabolism of C₁₉ Steroids in Rat Liver

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The steroid 16α-hydroxylase system in mammalian liver

Cited by 58 publications

References 11 publications

The influence of pyrogen-induced fever on salicylamide metabolism in man

The influence of pyrogen-induced fever on salicylamide metabolism in man

Studies on the Metabolism of C19‐Steroids in Rat Liver

Studies on the Metabolism of C19 Steroids in Rat Liver

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Studies on the Metabolism of C₁₉‐Steroids in Rat Liver

Studies on the Metabolism of C₁₉ Steroids in Rat Liver