Original Article

Journal of Investigative Dermatology (1991) 97, 447–453; doi:10.1111/1523-1747.ep12481411

In Vitro Cutaneous Biotransformation of Propranolol

Michel Corimer, Philip W Ledger, Jean Paul Marty and Alfred Arnkraut

ALZA Corporation, Palo Alto, California, U.S.A.

Received 9 November 1990; Accepted 4 April 1991.

Top

Abstract

The metabolism of propranolol by human skin and by several cell preparations has been investigated in vitro. The major metabolites produced by human skin in organ culture and by keratinocytes were N-desisopropytpropranolol (DIP), propranolol glycol (GLY) and naphthoxylactic acid (NLA). formation of GLY and NLA was linear with incubation time up to 6 d and was directly proportional to propranolol concentration. Fibroblasts and melanocytes also produced GLY and NLA, but appeared to have lower propranolol-biotrans-forming activity than keratinocytes. The three metabolites detected arise from side-chain oxidation of propranolol and the use of specific enzyme inhibitors determined that monoamine oxidase and cytochrome P450 isozymes are involved in their formation. Aldehyde and alcohol dehydrogenases are also probably involved in the formation of NLA and GLY, but attempts to inhibit these enzyme systems were inconclusive, possibly due to the chemical instability of the intermediate aldehyde resulting from monoamine oxidase activity. No evidence was found for conjugation or ring oxidation by the skin or isolated cells. Induction of keratinocyte differentiation with Ca++ or phorbol ester treatment resulted in an increase of overall biotransformation and the NLA/GLY ratio.

Top

References

  1. Martin, RJ, Denyer, SP, Hadgraft, J: Skin metabolism of topically applied compounds. Int J Pharm 1987 39: 23–32,  | Article | ChemPort |
  2. Coomes, MW, Norling, AH, Pohl, RJ, Müller, D, Fouts, JR: Foreign compound metabolism by isolated skin cells from the hairless mouse. J Pharm Exp Therap 1983 225: 770–777,  | ChemPort |
  3. Milewich, L, Kaimal, V, Shaw, CB, Sontheimer, RD: Epidermal keratinocytes: a source of 5plusminus-dihydrotestosterone production in human skin. J Clin Endocrinol Metab 1986 62: 739–746,  | PubMed | ISI | ChemPort |
  4. Thiele, B, Merk, HF, Bonnekoh, B, Mahrle, G, Steigleder, GK: Epidermal cell growth-dependent arylhydrocarbon-hydrolase (AHH) activity in vitro. Arch Dermatol Res 1987 279: 521–523,  | Article | PubMed | ChemPort |
  5. Stevens, CS, DeVillez, RL: Enzymology, with applications to dermatology. Int J Dermatol 1980 19: 295–309,  | PubMed | ChemPort |
  6. Pannatier, A, Testa, B, Etter, J-C: Enzymatic hydrolysis by mouse skin homogenates: structure-metabolism relationships of para-nitrobenzoate esters. Int J Pharmaceutics 1981 8: 167–174,  | Article | ChemPort |
  7. Valia, KH, Tojo, K, Chien, YW: Long-term permeation kinetics of estradiol: (III) kinetic analyses of the simultaneous skin permeation and bioconversion of estradiol esters. Drug Devel Indust Pharm 1985 11: 1133–1173,  | ChemPort |
  8. Weibel, H, Hansen, J, Andersen, KE: Cross-sensitization patterns in guinea pigs between cinnamaldehyde, cinnamyl alcohol and cinnamic acid. Acta Dermatol Venereol (Stockh) 1989 69: 302–307,  | ChemPort |
  9. Schmidt, RJ, Khan, L: Evidence for the existence of prohapten-activating enzyme in the skin: induction of contact sensitivity to monocrotaline in mice. In: Frosch PJ, Dooms-Goossens A, Lachapelle J-M, Rycroft RJG, Scheper RJ (eds.). Current Topics in Contact Dermatitis 1989, New York, Springer-Verlag, pp 24–30,
  10. Walle, T, Walle, UK, Olanoff, LS: Quantitative accounts of propranolol metabolism in urine of normal man. Drug Metab Dispos 1985 13: 204–209,  | PubMed | ChemPort |
  11. Vu, VT, Abramson, FP: The pathways of propranolol metabolism in dog and rat liver 10,000g supernatant fractions. Drug Metab Dispos 1980 8: 300–304,  | PubMed | ChemPort |
  12. de Mey, C, Enterling, D, Ederhof, M, Wesche, H, Osterwald, H: Transdermal delivery of mepindolol and propranolol in normal man. Drug Res 1989 39: 1505–1508,  | ChemPort |
  13. Vlasses, PH, Ribeiro, LGT, Rotmensch, HH, Bondi, JV, Loper, AE, Hichens, M, Dunlay, MC, Ferguson, RK: Initial evaluation of transdermal timolol: serum concentrations and beta-blockade. J Cardiovasc Pharmacol 1985 7: 245–250,  | PubMed | ChemPort |
  14. Joost, T, Middelkamp, J, Ros, FE: Dermatitis as a side effect of long term topical treatment with certain beta-blocking agents. Br J Dermatol 1979 101: 171–177,  | PubMed |
  15. Groot, AC, Conemans, J: Contact allergy to metipranolol. Contact Dermatitis 1988 18: 107–108,  | Article | PubMed |
  16. Boyce, ST, Ham, RG: Calcium-regulated differentiation of normal human epidermal keratinocytes in chemically defined clonal culture and serum-free serial culture. J Invest Dermatol 1983 81: 33S–40S,  | Article | PubMed | ChemPort |
  17. Reano, A, Ledger, PW, Bonnefoy, JY, Thivolet, J: Con A- and PNA-binding glycoproteins of human epidermis. J Invest Dermatol 1984 83: 202–205,  | Article | PubMed | ChemPort |
  18. Boyce, ST, Ham, RG: Cultivation, frozen storage and clonal growth of normal human epidermal keratinocytes in serum-free media. J Tissue Culture Methods 1985 9: 83–92,  | Article |
  19. Bennett, DC, Bridges, K, McKay, IA: Clonal separation of mature melinocytes from premelanocytes in a diploid human cell strain: spontaneous and induced pigmentation of premelanocytes. J Cell Sci 1985 77: 167–183,  | PubMed | ISI | ChemPort |
  20. White, R, Hu, F, Roman, NA: False dopa reaction in studies of mammalian tyrosinase: some characteristics and precautions. Stain Technology 1983 58: 13–19,  | PubMed | ChemPort |
  21. Lowry, OH, Rosebrough, NJ, Farr, AL, Randall, RJ: Protein measurement with the folin phenol reagent. J Biol Chem 1951 193: 265–275,  | PubMed | ISI | ChemPort |
  22. Swisher, DS, Cormier, M, Johnson, J, Ledger, PW: A cytotoxicity assay using normal, human keratinocytes: characterization and applications, Vol. 4. In: Maibach HI, Lowe NJ (eds.). Models in Dermatology 1988 1989, Karger, Basel, pp 131–137,
  23. Parkinson, EK, Pera, MF, Emmerson, A, Gorman, PA: Differential effects of complete and second-stage tumour promoters in normal but not transformed human and mouse keratinocytes. Carcinogenesis 1984 5: 1071–1077,  | PubMed | ChemPort |
  24. Cramb, G: Selective lysosomal uptake and accumulation of the betaadrenergic antagonist propranolol in cultured and isolated cell systems. Biochem Pharmacol 1986 35: 1365–1372,  | Article | PubMed | ChemPort |
  25. Scriba, GKE, Borchardt, RT: Metabolism of catecholamine esters by cultured bovine brain microvessel endothelial cells. J Neurochem 1989 53: 610–615,  | PubMed | ChemPort |
  26. Goldszer, F, Tindell, GL, Walle, UK, Walle, T: Chemical trapping of labile aldehyde intermediates in the metabolism of propranolol and oxprenolol. Res Commun Chem Pathol Pharmacol 1981 34: 193–205,  | PubMed | ChemPort |
  27. Walle, T, Ishizaki, T, Gaffney, TE: Isopropylamine, a biologically active deamination product of propranolol in dogs: identification of deuterated and unlabeled isopropylamine by gas chromatography-mass spectrometry. J Pharmacol Exp Ther 1972 183: 508–512,  | PubMed | ChemPort |
  28. Fujita, S, Usui, T, Suzuki, M, Hirasawa, M, Mori, Y, Naganuma, H, Suzuki, T: Induction of hepatic microsomal propranolol N-desisopropylase activity by 3-methylcholanthrene and sudan III. Biochem Biophys Res Commun 1982 105: 1233–1239,  | Article | PubMed | ChemPort |
  29. Guillouzo, A, Bégué, J-M, Maurer, G, Koch, P: Identification of metabolic pathways of pindolol and fluperlapine in adult human hepatocyte cultures. Xenobiotica 1988 18: 131–139,  | PubMed | ChemPort |
  30. McCormick, DJ, Fitzgerald, TC, McKillop, D: The metabolism of propranolol (ICI 45,520, InderalTM) and xamoterol (ICI 118,587, CorwinTM) by isolated rat hepatocytes: in vivo-in vitro correlations. Xenobiotica 1988 18: 1401–1412,  | PubMed | ChemPort |
  31. Hákanson, R, Müller, H: On metabolism of noradrenaline in the skin: activity of catechol-O-methyl transferase and monoamine oxidise. Acta Dermatol Venereol (Stockh) 1963 43: 552–555,
  32. Gazith, J, Cavey, MT, Cavey, D, Shroot, B, Reichert, U: Characterization of the beta-adrenergic receptors of cultured human epidermal keratinocytes. Biochem Pharmacol 1983 32: 3397–3403,  | Article | PubMed | ISI | ChemPort |
  33. Yasuda, K, Montagna, W: Histology and cytochemistry of human skin. XX. The distribution of monoamine oxidase. J Histochem Cytochem 1960 8: 356–366,  | PubMed | ChemPort |
  34. Siegenthaler, G, Saurat, J-H, Ponec, M: The formation of retinoic acid from retinol in relation to the differentiation state of cultured human keratinocytes. In: Reichert U, Shroot B (eds.). Pharmacology of Retinoids in the Skin 1989, Pharmacol Skin. Karger, Basel, 3: pp 52–55,
  35. Corbo, M, Liu, J-C, Chien, YW: Bioavailability of propranolol following oral and transdermal administration in rabbits. J Pharmaceur Sci 1990 79: 584–587,  | ChemPort |
  36. Singer, TS: Mitochondrial monoamine oxidase. Isolation, assay, properties, mechanism, and unresolved questions. In: Zakim D, Vessex DA (eds.). Biochemical Pharmacology and Toxicology 1985, John Wiley & Sons, New York, 1: pp 229–263,  | ChemPort |

Extra navigation

.
ADVERTISEMENT