Effect of inducers and inhibitors of monooxygenase on the hydroxylation of prostaglandin in the guinea pig. Evidence for several monooxygenases catalyzing ω- and ω-1-hydroxylation

D. Kupfer, G. K. Miranda, Javier Navarro, D. E. Piccolo, A. D. Theoharides

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Abstract

The incubation of prostaglandins (PG's) with liver microsomes from guinea pigs treated with inducers of monooxygenase (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), benzo[a]pyrene (benzpyrene), or a mixture of chlorinated biphenyls (Aroclor 1254) exhibited marked elevation of 19-hydroxylation of PGE 1, PGE 2, PGA 1, and PGA 2 without affecting significantly 20-hydroxylation. However, with respect to effects on hydroxylation of a variety of xenobiotics, benzpyrene and Aroclor treatments differed markedly; whereas Aroclor treatment elevated the demethylation of ethylmorphine, benzphetamine, and p-chloro-N-methylaniline (PCMA), benzpyrene treatment had no effect on demethylation of ethylmorphine and only a marginal effect on that of PCMA. Both inducers elevated benzpyrene hydroxylation. By contrast, treatment with phenobarbital did not affect the hepatic microsomal PG's hydroxylation, although the hydroxylation of benzpyrene and the demethylation of ethylmorphine, benzphetamine, and PCMA were enhanced. Also, the hydroxylation of PG's by kidney cortex microsomes was not affected by either benzpyrene or Aroclor treatment. Inhibitors of monooxygenase were used to help delineate the type of monooxygenases induced. At low levels of α-naphthoflavone (ANF), benzpyrene hydroxylation in control- and Aroclor-treated guinea pigs was only little affected; by contrast, the same concentration of ANF markedly inhibited benzpyrene hydroxylation in benzpyrene-treated guinea pigs. On the other hand, metyrapone was most inhibitory in control guinea pigs. Support for the conclusion that benzpyrene induces in the guinea pig a hepatic monooxygenase with different characteristics than that found in control animals was provided by the observation that ANF (10 μM) inhibited PGE 1 hydroxylation more pronouncedly in liver microsomes from benzpyrene-treated than from Aroclortreated guinea pigs or controls. In addition, in benzpyrene and Aroclor-treated guinea pigs, ANF inhibited the (ω-1)-hydroxylation more pronouncedly than that of ω-hydroxylation. By contrast, metyrapone appeared to inhibit ω-hydroxylation more effectively than (ω-1)-hydroxylation. These results indicate that in the guinea pig, hydroxylation of PG's at the ω (20-) and ω-1 (19-) positions is catalyzed by different monooxygenases and that the inducers tested affect several hepatic monooxygenases with different specificities toward xenobiotics; however, with respect to PG's only the enzyme(s) involved in the 19-hydroxylation is affected.

Original languageEnglish (US)
Pages (from-to)10405-10414
Number of pages10
JournalJournal of Biological Chemistry
Volume254
Issue number20
StatePublished - 1979
Externally publishedYes

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Hydroxylation
Mixed Function Oxygenases
Prostaglandins
Benzo(a)pyrene
Guinea Pigs
Aroclors
Ethylmorphine
Atrial Natriuretic Factor
Prostaglandins E
Benzphetamine
Prostaglandins A
Metyrapone
DDT
Liver Microsomes
Xenobiotics
Liver
Chlorodiphenyl (54% Chlorine)
Kidney Cortex
Phenobarbital
Microsomes

ASJC Scopus subject areas

  • Biochemistry

Cite this

Effect of inducers and inhibitors of monooxygenase on the hydroxylation of prostaglandin in the guinea pig. Evidence for several monooxygenases catalyzing ω- and ω-1-hydroxylation. / Kupfer, D.; Miranda, G. K.; Navarro, Javier; Piccolo, D. E.; Theoharides, A. D.

In: Journal of Biological Chemistry, Vol. 254, No. 20, 1979, p. 10405-10414.

Research output: Contribution to journalArticle

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N2 - The incubation of prostaglandins (PG's) with liver microsomes from guinea pigs treated with inducers of monooxygenase (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), benzo[a]pyrene (benzpyrene), or a mixture of chlorinated biphenyls (Aroclor 1254) exhibited marked elevation of 19-hydroxylation of PGE 1, PGE 2, PGA 1, and PGA 2 without affecting significantly 20-hydroxylation. However, with respect to effects on hydroxylation of a variety of xenobiotics, benzpyrene and Aroclor treatments differed markedly; whereas Aroclor treatment elevated the demethylation of ethylmorphine, benzphetamine, and p-chloro-N-methylaniline (PCMA), benzpyrene treatment had no effect on demethylation of ethylmorphine and only a marginal effect on that of PCMA. Both inducers elevated benzpyrene hydroxylation. By contrast, treatment with phenobarbital did not affect the hepatic microsomal PG's hydroxylation, although the hydroxylation of benzpyrene and the demethylation of ethylmorphine, benzphetamine, and PCMA were enhanced. Also, the hydroxylation of PG's by kidney cortex microsomes was not affected by either benzpyrene or Aroclor treatment. Inhibitors of monooxygenase were used to help delineate the type of monooxygenases induced. At low levels of α-naphthoflavone (ANF), benzpyrene hydroxylation in control- and Aroclor-treated guinea pigs was only little affected; by contrast, the same concentration of ANF markedly inhibited benzpyrene hydroxylation in benzpyrene-treated guinea pigs. On the other hand, metyrapone was most inhibitory in control guinea pigs. Support for the conclusion that benzpyrene induces in the guinea pig a hepatic monooxygenase with different characteristics than that found in control animals was provided by the observation that ANF (10 μM) inhibited PGE 1 hydroxylation more pronouncedly in liver microsomes from benzpyrene-treated than from Aroclortreated guinea pigs or controls. In addition, in benzpyrene and Aroclor-treated guinea pigs, ANF inhibited the (ω-1)-hydroxylation more pronouncedly than that of ω-hydroxylation. By contrast, metyrapone appeared to inhibit ω-hydroxylation more effectively than (ω-1)-hydroxylation. These results indicate that in the guinea pig, hydroxylation of PG's at the ω (20-) and ω-1 (19-) positions is catalyzed by different monooxygenases and that the inducers tested affect several hepatic monooxygenases with different specificities toward xenobiotics; however, with respect to PG's only the enzyme(s) involved in the 19-hydroxylation is affected.

AB - The incubation of prostaglandins (PG's) with liver microsomes from guinea pigs treated with inducers of monooxygenase (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), benzo[a]pyrene (benzpyrene), or a mixture of chlorinated biphenyls (Aroclor 1254) exhibited marked elevation of 19-hydroxylation of PGE 1, PGE 2, PGA 1, and PGA 2 without affecting significantly 20-hydroxylation. However, with respect to effects on hydroxylation of a variety of xenobiotics, benzpyrene and Aroclor treatments differed markedly; whereas Aroclor treatment elevated the demethylation of ethylmorphine, benzphetamine, and p-chloro-N-methylaniline (PCMA), benzpyrene treatment had no effect on demethylation of ethylmorphine and only a marginal effect on that of PCMA. Both inducers elevated benzpyrene hydroxylation. By contrast, treatment with phenobarbital did not affect the hepatic microsomal PG's hydroxylation, although the hydroxylation of benzpyrene and the demethylation of ethylmorphine, benzphetamine, and PCMA were enhanced. Also, the hydroxylation of PG's by kidney cortex microsomes was not affected by either benzpyrene or Aroclor treatment. Inhibitors of monooxygenase were used to help delineate the type of monooxygenases induced. At low levels of α-naphthoflavone (ANF), benzpyrene hydroxylation in control- and Aroclor-treated guinea pigs was only little affected; by contrast, the same concentration of ANF markedly inhibited benzpyrene hydroxylation in benzpyrene-treated guinea pigs. On the other hand, metyrapone was most inhibitory in control guinea pigs. Support for the conclusion that benzpyrene induces in the guinea pig a hepatic monooxygenase with different characteristics than that found in control animals was provided by the observation that ANF (10 μM) inhibited PGE 1 hydroxylation more pronouncedly in liver microsomes from benzpyrene-treated than from Aroclortreated guinea pigs or controls. In addition, in benzpyrene and Aroclor-treated guinea pigs, ANF inhibited the (ω-1)-hydroxylation more pronouncedly than that of ω-hydroxylation. By contrast, metyrapone appeared to inhibit ω-hydroxylation more effectively than (ω-1)-hydroxylation. These results indicate that in the guinea pig, hydroxylation of PG's at the ω (20-) and ω-1 (19-) positions is catalyzed by different monooxygenases and that the inducers tested affect several hepatic monooxygenases with different specificities toward xenobiotics; however, with respect to PG's only the enzyme(s) involved in the 19-hydroxylation is affected.

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