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Lack of effect of phenobarbitone treatment on metabolism and brain uptake of delta-aminolaevulinic acid in rats
Lack of effect of ph~llobarbitone
treatment
on
me~dbolism and brain uptake of delta-aminolae~ulini~ acid in rats (Rccyir~d
7S
O~r~h~i~
1976, ww/~r~~d 14 \‘orcw/~c~~ 19761
Short Table
communications
1. Etrect of phenobarbitone on tissue uptake. of administered delta-aminolaevolinic
Determination Hepatic microsomal cytochromc P-450 (nmole,!g liver) Serum ALA (~molejml) Brain ALA (nmole/g) Liver ALA (/lmole!g) Urinary ALA (/tmole;:24 hr) day 2 day 3 day 4 Urinarq,PBG (pmole!_4 hr) day 2 day 3 day 4
Controls?
x03 metabolism and urinary acid in the rat*
Phenobarbitone-t treated
excretion
Significance
14 * 2.4
37 f 1.4
2.3 & 0.45
2.5 _t 0.22
P > 0.1
39 _+ 5.2
33 * 4.5
P > 0.1
3.6 f 0.58
3.4 f 0.23
P > 0.1
490 & 4X 390 i_ 31 340 f 154
P > 0.1 P > 0.1 P > 0.1
27 * 2.4 24 + 3.X 24 f 5.X
P > 0.1 P > 0.1 P > 0.1
390 * 56 390 * 11 330 f 26
21 * 4.7 20 + 2.3 17 f 1.7
P < 0.001
* All values represent mean + SD. for three rats. + Control animals received saline. Phenobarbitone dosage was 50 mg/kg daily. Both groups received ALA intraperitoneally (500mg/kg) twice daily from day 2. Animals were sacrificed by decapitation on day 5, 30 min after final doses of saline, phenobarbitone and ALA. and some steroids, have been implicated in the preclpitation of the acute neuropsychiatric symptomatology of the hereditary hepatic porphyrias. This study was designed to test the proposal that the mechanism of action of such drugs might be (i) to promote neural uptake of porphyrin precursors which have been claimed to be potentially neurotoxic or (ii) to alter the metabolism of porphyrin prccursors with resultant formation of neurotoxic products. Rats were treated daily with phenobarbitonc and delta-aminolaevulinic acid (ALA) for 5 days. Phenobarbitone treatment had no significant effect on ALA metabolism and excretion or on ALA uptake into brain tissue. No significant behavioural effects other than those attributable to phenobarbitone alone were observed. These results do not support the suggestion that porphyrinogenic drugs may precipitate acute neuropathic effects in the hereditary hepatic porphyrias through altering porphyrin precursor metabolism or uptake of these compounds by neural tissue.
Acknowledgemellrs-~The authors thank the South African Medical Research Council for financial assistance. and the University of Stellenbosch and the Cape Provincial Administration for the use of facilities.
Department 0fChrmicul
Patholof~~,
Unirersit): ofStr//rnhoscb. P.O. Box 63. Tygerbrrg 7505, South Africa
VIVII’NNI A. PI KC‘\~ BRIAN C. SHANLEY*
1. L. Eales, S. Afr. J. Lab. c/in. Med. 17, 120 (1971). 2. S. Kramer, D. Becker and D. Viljoen. S. 4fr. merl. J. 47, 1735 (1973).
*Correspondence
should
be addressed
to this author.
R. A. 3. D. S. Feldman. R. D. Levere. J. S. Lieberman. Cardinal and C. J. Watson. Proc,. ~JI~I. .Actrt/. Sci. U.S.A. 68, 383 (1971). and S. Kramer. S. Air. 4. D. M. Becker. N. Goldstuck md. J. 49, 1790 (1975). A. C. Neethling, V. A. Percy and M. 5. B. C.‘Shanley. Carstens. S. ,4.fti. ,nrt/. J. 49, 576 (1975). in 6. B. C. Shanley. V. A. Percy and A. C. Neethling. Porphyvi/l\ irl Hunttr~~ Discwe.\ (Ed. M. Doss). p. 155. S. Karger AC, Base1 (1976). M. R. Moore and A. Goldberg. Scott. 7. F. B. McGlllion. merl. J. 18, 133 (1973). L. Wetterburg. A. Yuwilcr and W. D. 8. R. J. Marcus. Winters. Elcctrot~xwph. c/in. ,%‘clrroph~.sio/. 29, 602 (1970). J. J. Bradshaw. J. A. Marsh. G. G. 9. K. M. Ivanetich. Harrison and L. S. Kaminsky. Biochum. Phtrmtrc. 25, 773 (1976). IO. K. M. Ivanctich. J. J. Bradshaw. J. A. Marsh and L. S. Kaminsky. Uiochr’~t~. Pl~or~nc~c. 25. 779 (1976). and C. J. Wat1 I. K. Miyagi. R. Cardinal. I. Bosscnmaler son. J. Lob. din. Mrtl. 78, 683 (1971). 12. H. S. Marver, D. P. Tschudy. M. G. Perlroth, A. Collins and G. Hunter, Antr/~,r. Biochrm. 14, 53 (1966). 13. J. R. Fry and J. W. Bridges. dr~tr/xr. Biochc,nz. 67, 309 (1975). 14. T. Omura and R. Sato. J. hid. Cbcw. 239, 2370 (1964). 15. M. R. Moore, F. B. McGillion and A. Goldberg, in Porphwi/r\ irt Hwt~tr~~ Disc~r.w.~ (Ed. M. Doss). p. 14X. S. Kargcr AC. Bascl (1976). 16. H. S. Marver and R. Schmid. in TRIP Mrrc~bolic Basis of Inhrritrd Di.ww (Eds. J. B. Stanbury. J. B. Wyngaarden and D. S. Frederickson) 3rd cd. p. 1087. McGraw-Hill. New York (1972). and D. Sciarra. Brtrk 68, 1 (1945). 17. D. Denny-Brown 18. J. B. Gibson and A. Goldberg, J. Path. But. 71, 495 (1956). 19. J. B. Cavanagh and R. S. Mellick, J. Neural. Nerosurg. Ps!,cbiot. 28, 320 (1965). 20. V. P. Sweeney. M. A. Pathak and A. K. Asbury. Bruin 93, 369 (1970).
treatment
on
me~dbolism and brain uptake of delta-aminolae~ulini~ acid in rats (Rccyir~d
7S
O~r~h~i~
1976, ww/~r~~d 14 \‘orcw/~c~~ 19761
Short Table
communications
1. Etrect of phenobarbitone on tissue uptake. of administered delta-aminolaevolinic
Determination Hepatic microsomal cytochromc P-450 (nmole,!g liver) Serum ALA (~molejml) Brain ALA (nmole/g) Liver ALA (/lmole!g) Urinary ALA (/tmole;:24 hr) day 2 day 3 day 4 Urinarq,PBG (pmole!_4 hr) day 2 day 3 day 4
Controls?
x03 metabolism and urinary acid in the rat*
Phenobarbitone-t treated
excretion
Significance
14 * 2.4
37 f 1.4
2.3 & 0.45
2.5 _t 0.22
P > 0.1
39 _+ 5.2
33 * 4.5
P > 0.1
3.6 f 0.58
3.4 f 0.23
P > 0.1
490 & 4X 390 i_ 31 340 f 154
P > 0.1 P > 0.1 P > 0.1
27 * 2.4 24 + 3.X 24 f 5.X
P > 0.1 P > 0.1 P > 0.1
390 * 56 390 * 11 330 f 26
21 * 4.7 20 + 2.3 17 f 1.7
P < 0.001
* All values represent mean + SD. for three rats. + Control animals received saline. Phenobarbitone dosage was 50 mg/kg daily. Both groups received ALA intraperitoneally (500mg/kg) twice daily from day 2. Animals were sacrificed by decapitation on day 5, 30 min after final doses of saline, phenobarbitone and ALA. and some steroids, have been implicated in the preclpitation of the acute neuropsychiatric symptomatology of the hereditary hepatic porphyrias. This study was designed to test the proposal that the mechanism of action of such drugs might be (i) to promote neural uptake of porphyrin precursors which have been claimed to be potentially neurotoxic or (ii) to alter the metabolism of porphyrin prccursors with resultant formation of neurotoxic products. Rats were treated daily with phenobarbitonc and delta-aminolaevulinic acid (ALA) for 5 days. Phenobarbitone treatment had no significant effect on ALA metabolism and excretion or on ALA uptake into brain tissue. No significant behavioural effects other than those attributable to phenobarbitone alone were observed. These results do not support the suggestion that porphyrinogenic drugs may precipitate acute neuropathic effects in the hereditary hepatic porphyrias through altering porphyrin precursor metabolism or uptake of these compounds by neural tissue.
Acknowledgemellrs-~The authors thank the South African Medical Research Council for financial assistance. and the University of Stellenbosch and the Cape Provincial Administration for the use of facilities.
Department 0fChrmicul
Patholof~~,
Unirersit): ofStr//rnhoscb. P.O. Box 63. Tygerbrrg 7505, South Africa
VIVII’NNI A. PI KC‘\~ BRIAN C. SHANLEY*
1. L. Eales, S. Afr. J. Lab. c/in. Med. 17, 120 (1971). 2. S. Kramer, D. Becker and D. Viljoen. S. 4fr. merl. J. 47, 1735 (1973).
*Correspondence
should
be addressed
to this author.
R. A. 3. D. S. Feldman. R. D. Levere. J. S. Lieberman. Cardinal and C. J. Watson. Proc,. ~JI~I. .Actrt/. Sci. U.S.A. 68, 383 (1971). and S. Kramer. S. Air. 4. D. M. Becker. N. Goldstuck md. J. 49, 1790 (1975). A. C. Neethling, V. A. Percy and M. 5. B. C.‘Shanley. Carstens. S. ,4.fti. ,nrt/. J. 49, 576 (1975). in 6. B. C. Shanley. V. A. Percy and A. C. Neethling. Porphyvi/l\ irl Hunttr~~ Discwe.\ (Ed. M. Doss). p. 155. S. Karger AC, Base1 (1976). M. R. Moore and A. Goldberg. Scott. 7. F. B. McGlllion. merl. J. 18, 133 (1973). L. Wetterburg. A. Yuwilcr and W. D. 8. R. J. Marcus. Winters. Elcctrot~xwph. c/in. ,%‘clrroph~.sio/. 29, 602 (1970). J. J. Bradshaw. J. A. Marsh. G. G. 9. K. M. Ivanetich. Harrison and L. S. Kaminsky. Biochum. Phtrmtrc. 25, 773 (1976). IO. K. M. Ivanctich. J. J. Bradshaw. J. A. Marsh and L. S. Kaminsky. Uiochr’~t~. Pl~or~nc~c. 25. 779 (1976). and C. J. Wat1 I. K. Miyagi. R. Cardinal. I. Bosscnmaler son. J. Lob. din. Mrtl. 78, 683 (1971). 12. H. S. Marver, D. P. Tschudy. M. G. Perlroth, A. Collins and G. Hunter, Antr/~,r. Biochrm. 14, 53 (1966). 13. J. R. Fry and J. W. Bridges. dr~tr/xr. Biochc,nz. 67, 309 (1975). 14. T. Omura and R. Sato. J. hid. Cbcw. 239, 2370 (1964). 15. M. R. Moore, F. B. McGillion and A. Goldberg, in Porphwi/r\ irt Hwt~tr~~ Disc~r.w.~ (Ed. M. Doss). p. 14X. S. Kargcr AC. Bascl (1976). 16. H. S. Marver and R. Schmid. in TRIP Mrrc~bolic Basis of Inhrritrd Di.ww (Eds. J. B. Stanbury. J. B. Wyngaarden and D. S. Frederickson) 3rd cd. p. 1087. McGraw-Hill. New York (1972). and D. Sciarra. Brtrk 68, 1 (1945). 17. D. Denny-Brown 18. J. B. Gibson and A. Goldberg, J. Path. But. 71, 495 (1956). 19. J. B. Cavanagh and R. S. Mellick, J. Neural. Nerosurg. Ps!,cbiot. 28, 320 (1965). 20. V. P. Sweeney. M. A. Pathak and A. K. Asbury. Bruin 93, 369 (1970).