Patai S., Rappoport Z. 1997 The chemistry of functional groups. The chemistry of double-bonded functional groups / 1625 166

26. N-Oxidative transformations of CDN groups

1655

N O-sulfation of minoxidil in the presence of adenosine-30-phospho-50-phosphosulfate (PAPS) (equation 24). The enzyme-synthetized product was identical to authentic N O- sulfate with respect to chromatographic behavior and mass spectral characteristics and was split to minoxidil when treated with sulfatase183. The pH optimum for minoxidil N O-sulfation was about 8.0. Enzyme activity in crude preparations was maintained for several months during storage at 76 °C, while activity of partially purified enzyme was lost under these conditions183.

	O					OSO3	−
H2 N	N	NH2	+ PAPS		H2 N	N+	NH2
							+ PAP

(24)

N	N
Pip	Pip
(19)

Sulfotransferase activity is not restricted to minoxidil. The ability of other pyrimidine-, as well as pyridine-, triazineand imidazole N-oxides to serve as substrates was investigated using soluble liver preparation and PAPS. The variety of structures studied indicated that heteroaromatic N-oxides are generally metabolized by sulfotransferases183. Presumably, all of the heterocycles tested were conjugated via their N-oxide oxygens.

B. Nonenzymatic Processes

1. Nucleophilic reactions

Oximes are known to exert nucleophilic attack at appropriate targets. An elegant example of this is offered by the oxime-induced reactivation of the phosphorylated esteratic site of acetylcholinesterase (AChE; EC 3.1.1.7). Quasi-irreversible phosphorylation of AChE is brought about by highly toxic organophosphorus compounds used as pesticides or chemical warfare agents (GV, sarin, soman, tabun)184. Successful regeneration of modified AChE has been reported using pralidoxime (PAM; 16) as a reactivator. The restoration mechanism has been thought to include close apposition of the nucleophile to the attached phosphorus to permit attack, the oxime-phosphonate then being split off; the latter intermediate decays to release nitrile and organophosphate185 (equation 25). It is interesting to note that the Z-isomer of pralidoxime was inactive, while the E-form proved to be a highly efficient reactivator. There was a spread of a factor 2 in reaction rate between the 2-, 3- and 4-substituted derivatives185. A number of bis-quarternary oximes, such as obidoxime (toxogonin; 17), were subsequently shown to be even more potent reactivators and antidotes for nerve gas poisoning186,187. However, the failure of obidoxime to appreciably reactivate AChE blocked by soman188 prompted the synthesis of new pyridinium oximes. Thus, a variety of asymmetric bis-pyridinium aldoximes (53), referred to as H-oximes189, have been shown to possess good antidotal properties, of which HI-6 is regarded as a promising compound against poisoning by soman, sarin and GV189 192. The oxime HLo7¨ closely resembles HI-6, but bears an additional aldoxime functionality at the 4-position (54) and appears to be the first broad-spectrum reactivator193.

1656

Peter Hlavica and Michael Lehnerer

O

O

O

O

AChE

C

NH CH

C

AChE

C

NH

CH

C

CH2

O

CH2

OR1

O−

O

P

H

OR2

H

O

+ N

C N O−

+ N

C N O P OR1

Me

Me

(25)

OR2

O

+ N

C

N +

HO

OR1

P

Me

OR2

HON

CH

CONH2

R

HON

HC

+ N

+ N

HON

HC

+ N

+ N

CH2

O

CH2

CH2

O

CH2

(53)

(54)

Reactivity of phosphorylated AChE toward pralidoxime has been found also to vary with the nature of the phosphoryl group, increasing in the order di-Pri-<di-Et-<di-Me- phosphoryl-AChE. Moreover, phosphorylated AChE can undergo fairly rapid “aging”, so that it becomes completely resistant to the action of oximes. This process is probably due to the loss of one alkyl or alkoxy group, leaving a much more stable monoalkylor monoalkoxyphosphorylated enzyme194. Phosphonates containing tertiary alkoxy groups are more prone to “aging” than their primary or secondary congeners195.

2. Photochemical reactions

Photolysis of heteroaromatic N-oxides has proved to be useful as a mechanistic model for enzymatic oxygen atom transfer reactions. Thus, irradiation with UV light of solutions containing naphthalene and pyridine N-oxide (40) resulted in the production of 1,2-naphthalene oxide and naphthol (equation 26), suggesting the intermediacy of arene oxides during oxygenation of aromatic compounds196. This system also effected aliphatic hydroxylations as well as sulfoxidations, reactions typical of monooxygenases. Aromatic

26. N-Oxidative transformations of CDN groups

1657

hydroxylations were also brought about when pyridazine N-oxide (44) or pyrazine N-oxide (45) served as the oxygen donors in the photolytic process196.

OH

			O
+		hν	and
	N		(26)

O

(40)

Irradiation with UV light of nitrones has been observed to induce rearrangement to yield oxaziridines and amides197 (equation 27). In this context, light exposure of the nitrones derived from the cyclic imino nitrogens in the methaqualone (33) and diazepam structure gave reactive oxaziridines, which were toxic to Salmonella typhimurium strain TA100198,199. Similarly, oxaziridine is the main product obtained upon irradiation of chlordiazepoxide (18). The intermediate induces DNA damage in bacterial test systems, reacts with SH-groups in compounds such as glutathione199 and is subject to irreversible binding to proteins200. Analogous light-induced transformation to a toxic oxaziridine has also been reported for the di-N-oxide olaquindox (49), which elicits severe photoallergic

reactions in animals and man164,201. Finally, oxaziridines can arise from the photolysis of purine N-oxides84.

H	−		O
	O		H
+		hν
C N			N			C				NHR	(27)
	R			R
						O

3. Radical reactions

Free radicals have been frequently recognized as being involved in the mechanism of toxicity of foreign compounds. However, many free radicals of biological interest are too reactive to permit direct observation. This difficulty can be overcome by using a diamagnetic organic molecule, such as a nitrone, to ‘trap’ the short-lived radical species and produce a more stable ‘spin adduct’. The latter is a nitroxide radical, the magnetic moment exerted by its unpaired electron being easily detected by electron paramagnetic resonance (EPR) spectrometry202,203.

Some more common nitrone spin traps are 5,5-dimethyl-1-pyrroline N-oxide (DMPO; 55), ˛-phenyl-tert-butylnitrone (PBN; 56a) and ˛-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN; 56b). As an example, the reaction of 55 with free radicals (Rž ) may be expressed as illustrated by equation 28. Spin adducts of this type will exhibit six-line EPR spectra with different hyperfine coupling constants for nitrogen and ˇ-hydrogen204. However, identification of the parent radicals can be difficult with nitrone spin traps because adducts derived from different radicals often have very similar EPR spectra. Rates of trapping of oxygen-centered radicals (O2 ž , HOOž , OHž , ROž ) by DMPO have been estimated to be within the order of 104 to 109 M 1 s 1, but adduct formation with carbon-, nitrogenand sulfur-centered radicals also proceeds at appreciable velocity204. Carefully designed

1658	Peter Hlavica and Michael Lehnerer

control experiments are essential if meaningful conclusion are to be drawn from spintrapping data for putative oxygen-centered radicals. Thus, air or H2O2 oxidation of nitrones following their hydration or nucleophilic transformation has been described to be a source of artefactual nitroxide radical formation, as is oxidation of the spin traps by trace amounts of iron and other heavy metals. The subject has been reviewed by Finkelstein and associates202.

Me

Me

R

+

R

•

Me

N

H

Me

N

H

(28)

O−

O•

(55)

Me

O−

+

(a) R = Ph

Me

H

RCH

NBut

+

N

+

(b) R = O−

N

O−

(55)(56)

VII. CONCLUSIONS

Compounds bearing N-oxygenated CDN functionalities exhibit interesting pharmacological and toxicological properties. Thus, some synthetic oximes exerting central nervous or antibacterial effects have been introduced as medicinal agents. Certain metabolically formed oximes, such as amidand guanidoximes, may have genotoxic activities inducing DNA single-strand breaks. Moreover, nitrones can bind covalently to proteins, and some congeners, such as diarylnitrones, release arylhydroxylamines upon their hydrolysis, which are known to be quite toxic. Oxaziridine intermediates, proposed to be precursors in enzymatic nitrone production or to arise from photolysis of nitrones, may be expected to react with cellular macromolecules to induce mutagenic, carcinogenic, immunological and other toxic processes.

There is widespread occurrence of heteroaromatic N-oxides in nature; many of them possess antibiotic potency while others are growth factors in microorganisms. In some cases, synthetic heteroaromatic N-oxides exhibit pharmacological activity greater than the parent amines and are currently used as drugs. Usually, metabolic N-oxide formation from aromatic heterocycles is regarded as a detoxification or deactivation reaction, leading to the production of stable water-soluble metabolites that are readily eliminated in the urine. However, there are examples in the literature of synthetic carcinogenic heteroaromatic N-oxides.

N-oxygenated CDN functionalities may be subject to further metabolic transformation through various reactions, such as reduction, oxidation, deamination, rearrangement or conjugation. Reduction of oximes and heteroaromatic N-oxides in vivo undoubtedly diminishes their release from the liver, and redox cycling in the sense of N-oxygenation followed by limited reduction might act as a sort of ‘metabolic buffer’. Oxidative cleavage of the CDNOH bond in certain amidand guanidoximes to liberate NO may be related to their ability to lower blood pressure. Sulfation of vasoactive azaheteroaromatic N-oxides most likely infers interesting pharmacological properties. In addition to the enzymatic processes described, nitrones and heteroaromatic N-oxides may undergo disposition by

26. N-Oxidative transformations of CDN groups

1659

post-enzymatic mechanisms, such as photolysis to produce reactive intermediates that elicit severe phototoxic effects in parts of the body exposed to sunlight.

N-Oxidative biotransformation of CDN functionalities as well as secondary metabolism of the N-oxygenated products formed is brought about by a multiplicity of enzyme systems, including oxidoreductases (P-450; FMO; xanthine oxidase; aldehyde oxidase), hydrolases and transferases. The interplay in the diverse organs of animal species of the various catalysts, characterized by definite substrate specificities, is likely to control the mode and/or extent to which metabolic turnover occurs, and this may serve to rationalize differences in the particular response to the pharmacological or toxicological actions of certain organic compounds containing N-oxygenated CDN groups.

VIII. REFERENCES

1.C. J. Parli, N. Wang and R. E. McMahon, J. Biol. Chem., 246, 6953 (1971).

2.B. Clement, Xenobiotica, 13, 467 (1983).

3.J. W. Gorrod and M. Ulgen, Drug. Metab. Rev., 26, 241 (1994).

4.M. A. Schwartz, E. Postma, S. J. Kolis and A. S. Leon, J. Pharm. Sci., 62, 1776 (1973).

5.V. M. Florence, E. W. Di Stefano, C. Y. Sum and A. K. Cho, Drug Metab. Dispos., 10, 312 (1982).

6.A. H. Beckett and G. G. Gibson, J. Pharm. Pharmacol., 29, 756 (1977).

7.L. A. Damani, P. A. Crooks, M. S. Shaker, J. Caldwell, J. D’Souza and R. L. Smith, Xenobiotica, 12, 527 (1982).

8.K. El-Ghomari and J. W. Gorrod, Eur. J. Drug Metab. Pharmacokin., 12, 253 (1987).

9.T. G. Altuntas and J. W. Gorrod, Pharm. Sci. Commun., 4, 117 (1994).

10.P. A. S. Smith, Open Chain Nitrogen Compounds, Part I, Benjamin, New York, 1965, p. 294.

11. L. A. Damani, in Metabolic Basis of Detoxication: Metabolism of Functional Groups (Eds.

W. B. Jakoby, J. R. Bend and J. Caldwell), Academic Press, New York, 1982, pp. 127 149.

12.C. Moreau and G. Mignonac, Ann. Chim. (Paris), 14, 322 (1920).

13.J. W. Gorrod and M. Christou, Xenobiotica, 16, 575 (1986).

14.B. Clement, M. H. Schultze-Mosgau, P. H. Richter and A. Besch, Xenobiotica, 24, 671 (1994).

15.J. W. Gorrod, Xenobiotica, 1, 349 (1971).

16.P. J. Watkins and J. W. Gorrod, Eur. J. Drug Metab. Pharmacokin., 12, 245 (1987).

17.P. Hlavica, Crit. Rev. Biochem., 12, 39 (1982).

18.J. W. Gorrod and L. A. Damani, Eur. J. Drug Metab. Pharmacokin., 5, 53 (1980).

19.F. F. Kadlubar, E. M. Mckee and D. M. Ziegler, Arch. Biochem. Biophys., 156, 46 (1973).

20.W. F. Smyth, in Biological Oxidation of Nitrogen (Ed. J. W. Gorrod), Elsevier, Amsterdam, 1978, pp. 281 292.

21.B. A. Halkier, H. L. Nielsen, B. Koch and B. L. Møller, Arch. Biochem. Biophys., 322, 369 (1995).

22.A. H. Beckett and N. N. Rahman, Xenobiotica, 7, 537 (1977).

23.A. H. Beckett, G. E. Navas and A. J. Hutt, Xenobiotica, 18, 61 (1988).

24.R. T. Coutts and S. H. Kovach, Biochem. Pharmacol., 26, 1043 (1977).

25.A. H. Beckett and K. Haya, J. Pharm. Pharmacol., 29, 89 (1977).

26.J. W. Gorrod and N. J. Gooderham, Xenobiotica, 15, 1021 (1985).

27.L. A. Damani, L. H. Patterson and J. W. Gorrod, J. Chromatogr., 155, 337 (1978).

28.D. A. Cowan, L. A. Damani and J. W. Gorrod, Biomedical Mass Spectrometry, 5, 551, (1978).

29.P. Hlavica, J. Mietaschk and I. Baden, Biochem. J., 204, 425 (1982).

30.M. A. Schwartz, T. H. Williams, S. J. Kolis, E. Postma and G. J. Sasso, Drug Metab. Dispos., 6, 647 (1978).

31.L. A. Damani, P. A. Crooks and D. A. Cowan, Biomedical Mass Spectrometry, 8, 270 (1981).

32.A. Assandri, A. Omodei-Sale, P. Ferrari, G. Tuan, A. Perazzi, A. Ripamonti and E. Martinelli,

Xenobiotica, 12, 19 (1982).

33.J. Wright, A. K. Cho and J. Gal, Xenobiotica, 7, 257 (1977).

34.H. B. Hucker, B. M. Michniewicz and R. E. Rhodes, Biochem. Pharmacol., 20, 2123 (1971).

35.R. M. Matsumoto and A. K. Cho, Biochem. Pharmacol., 31, 105 (1982).

36.B. C. Foster, R. T. Coutts and F. M. Pasutto, Xenobiotica, 19, 531 (1989).

37.R. C. Kammerer, Life Sci., 27, 2175 (1980).

1660	Peter Hlavica and Michael Lehnerer

38.A. H. Beckett and E. C. Chidomere, J. Pharm. Pharmacol., 29, 281 (1977).

39.T. Baba, H. Yamada, K. Oguri and H. Yoshimura, Xenobiotica, 17, 1029 (1987).

40.J. W. Gorrod and L. A. Damani, J. Chromatogr., 155, 349 (1978).

41.J. W. Gorrod and L. A. Damani, Xenobiotica, 9, 209 (1979).

42.J. De Graeve, J. E. Gielen, G. F. Kahl, K. H. Tuttenberg,¨ R. Kahl and B. Maume, Drug Metab. Dispos., 7, 166 (1979).

43.C. N. Reynolds, K. Wilson and D. Burnett, Xenobiotica, 6, 113 (1976).

44.G. Hawksworth and R. R. Scheline, Xenobiotica, 5, 389 (1975).

45.O. Sibbesen, B. Koch, B. A. Halkier and B. L. Møller, J. Biol. Chem., 270, 3506 (1995).

46.L. A. Sternson and F. Hincal, Biochem. Pharmacol., 27, 1919 (1978).

47.B. Clement and M. Zimmermann, Biochem. Pharmacol., 37, 4747 (1988).

48.B. Clement, F. Jung and H. Pfunder, Mol. Pharmacol, 43, 335 (1993).

49.B. Clement and M. Zimmermann, Xenobiotica, 17, 659 (1987).

50.B. Clement and F. Jung, Xenobiotica, 25, 443 (1995).

51.B. Clement and F. Jung, Drug Metab. Dispos., 22, 486 (1994).

52.B. Clement, M. H. Schultze-Mosgau and H. Wohlers, Biochem. Pharmacol, 46, 2249 (1993).

53.J. W. Gorrod and N. J. Gooderham, Xenobiotica, 17, 165 (1987).

54.E. H. Jeffery and G. J. Mannering, Mol. Pharmacol., 23, 748 (1983).

55.A. Bondon, T. L. Macdonald, T. M. Harris and F. P. Guengerich, J. Biol. Chem., 264, 1988 (1989).

56.B. J. Blaauboer and A. J. Paine, Xenobiotica, 10, 655 (1980).

57.M. S. Shaker, P. A. Crooks and L. A. Damani, J. Chromatogr., 237, 489 (1982).

58.T. J. Wilke, W. R. Jondorf and G. Powis, Xenobiotica, 19, 1013 (1989).

59.S. G. Kim, D. E. Williams, E. G. Schultz, S. Guzelian and R. F. Novak, J. Pharmacol. Exp. Ther., 246, 1175 (1988).

60.S. G. Kim, R. M. Philpot and R. F. Novak, J. Pharmacol. Exp. Ther., 259, 470 (1991).

61.P. A. Crooks, L. A. Damani and D. A. Cowan, J. Pharm. Pharmacol., 33, 309 (1981).

62.D. Lacroix, M. Desrochers, A. Castonguay and A. Anderson, Carcinogenesis, 14, 1639 (1993).

63.Z. Guo, T. J. Smith, H. Ishizaki and C. S. Yang, Carcinogenesis, 12, 2277 (1991).

64.S. P. Lam, F. Devinsky and J. W. Gorrod, Eur. J. Drug Metab. Pharmacokin., 12, 239 (1987).

65.S. P. Lam, D. J. Barlow and J. W. Gorrod, J. Pharm. Pharmacol., 41, 373 (1989).

66.D. A. Cowan, in Biological Oxidation of Nitrogen (Ed. J. W. Gorrod), Elsevier, Amsterdam, 1978, pp. 263 268.

67.B. Clement and T. Kampchen,¨ in N-Oxidation of Drugs. Biochemistry, Pharmacology, Toxicology

(Eds. P. Hlavica and L. A. Damani), Chapman and Hall, London, 1991, pp. 19 35.

68.G. R. Clemo and H. McIlwain, J. Chem. Soc. (London), 479 (1938).

69.H. P. Sigg and A. Toth, Helv. Chim. Acta, 50, 716 (1967).

70.T. Emery, Adv. Enzymol., 35, 135 (1971).

71.E. C. White and J. H. Hill, J. Bacteriol., 45, 433 (1943).

72.G. A. Snow, Biochem. J., 94, 160 (1965).

73.H. T. Shigeura and C. N. Gordon, J. Biol. Chem., 237, 1937 (1962).

74.J. D. Phillipson, in Biological Oxidation of Nitrogen in Organic Molecules (Eds. J. W. Bridges,

J. W. Gorrod and D. V. Parke), Taylor and Francis, London, 1972, pp. 107 135.

75. R. Seeger, in Allgemeine und Spezielle Pharmakologie und Toxikologie, sixth edition (Eds. W. Forth, D. Henschler, W. Rummel and K. Starke), BI Wissenschaftsverlag, Mannheim, 1992,

pp.836 841.

76.P. Jenner, in Biological Oxidation of Nitrogen (Ed. J. W. Gorrod), Elsevier, Amsterdam, 1978,

pp.383 398.

77.G. L. Mandell and M. A. Sande, in The Pharmacological Basis of Therapeutics, eighth edition (Eds. A. Goodman Gilman, T. W. Randall, A. S. Nies and P. Tylor), Pergamon Press, New York, 1990, pp. 1065 1097.

78.I. B. Wilson and S. Ginsburg, Biochim. Biophys. Acta, 18, 168 (1955).

79.R. I. Ellin, Gen. Pharmacol., 13, 457 (1982).

80.L. O. Randall, W. Schallek, G. A. Heise, E. F. Keith and R. E. Bagdon, J. Pharm. Exp. Ther., 129, 163 (1960).

81.W. Dittmar and G. Lohaus, Arzneim.-Forsch. (Drug Res.), 23, 670 (1973).

82.N. R. Banna and R. Kurkjian, Brain Res., 87, 114 (1975).

83.H. Endo, T. Ono and T. Sugimura, Recent Results Cancer Res., 34, 1 (1971).

26. N-Oxidative transformations of CDN groups

1661

84.G. B. Brown, Prog. Nucleic Acid Res. Mol. Biol., 8, 209 (1968).

85.M. Christou and J. W. Gorrod, in Biological Oxidation of Nitrogen in Organic Molecules (Eds. J. W. Gorrod and L. A. Damani), Ellis Horwood, Chichester, 1985, pp. 278 289.

86.B. Clement, M. Immel, H. Pfundner, S. Schmitt and M. Zimmermann, in N-Oxidation of Drugs. Biochemistry, Pharmacology, Toxicology (Eds. P. Hlavica and L. A. Damani), Chapman and Hall, London, 1991, pp. 185 205.

87.J. W. Gorrod and A. Raman, Drug Metab. Rev., 20, 307 (1989).

88.S. F. Sisenwine and C. O. Tio, Drug Metab. Dispos., 9, 37 (1981).

89.K. Wilson, M. Oram and C. N. Reynolds, in Biological Oxidation of Nitrogen (Ed. J. W. Gorrod), Elsevier, Amsterdam, 1978, pp. 145 150.

90.R. B. Franklin, L. G. Dring and R. T. Williams, Drug Metab. Dispos., 5, 223 (1977).

91.A. H. Beckett and A. H. Sheihk, J. Pharm. Pharmacol., 25, 171P (1973).

92.J. W. Gorrod and L. A. Damani, Xenobiotica, 9, 219 (1979).

93.R. F. Novak, K. L. Kaul and S. G. Kim, Drug Metab. Rev., 20, 781 (1989).

94.V. Neuhoff and F. Kohler,¨ Naunyn-Schmiedeberg’s Arch. Pharmak. Exp. Path., 254, 301 (1966).

95.P. Eyer and W. Hell, Xenobiotica, 13, 649 (1983).

96.S. Chaykin, M. Dagami, L. Johnson and M. Samli, J. Biol. Chem., 240, 932 (1965).

97.B. Petrack, P. Greengard and H. Kalinsky, J. Biol. Chem., 241, 2367 (1966).

98.S. Chaykin, M. Dagami, L. Johnson, M. Samli and J. Battaile, Biochim. Biophys. Acta, 100, 351 (1965).

99.E. Dagne and N. Castagnoli, J. Med. Chem., 15, 840 (1972).

100.P. A. F. Dixon, C. A. Joseph, S. E. Okereke and M. C. Enwelum, in Biological Oxidation of Nitrogen in Organic Molecules. Chemistry, Toxicology and Pharmacology (Eds. J. W. Gorrod and L. A. Damani), Ellis Horwood, Chichester, 1985, pp. 236 239.

101.J. I. Usansky and L. A. Damani, in Biological Oxidation of Nitrogen in Organic Molecules. Chemistry, Toxicology and Pharmacology (Eds. J. W. Gorrod and L. A. Damani), Ellis Horwood,

Chichester, 1985, pp. 231 235.

102. A. Castonguay, D. Lin, G. D. Stoner, P. Radok, K. Furuya, S. S. Hecht, H. A. J. Schut and

J.E. Klaunig, Cancer Res., 43, 1223 (1983).

103.D. E. Duggan, R. M. Noll, J. E. Baer, F. C. Novello and J. J. Baldwin, J. Med. Chem., 18, 900 (1975).

104.E. E. Essien and G. C. Afamefuna, Clin. Chem., 28, 1148 (1982).

105.M. A. Brooks, J. A. F. De Silva and L. D’Arconte, J. Pharm. Sci., 62, 1395 (1973).

106.J. P. Hubbell, M. L. Henning, M. E. Grace, C. A. Nichol and C. W. Sigel, in Biological Oxidation of Nitrogen (Ed. J. W. Gorrod), Elsevier, Amsterdam, 1978, pp. 177 182.

107.F. J. Wolf, J. J. Steffens, R. F. Alvaro and T. A. Jacob, Fed. Proc., 37, 814 (1978).

108.M. Nakagawa and M. Ando, Agric. Biol. Chem., 41, 1975 (1977).

109.G. R. Zins, D. W. Emmert and R. A. Walk, J. Pharmacol. Exp. Ther., 159, 194 (1968).

110.A. H. Beckett and P. M. Belanger,´ J. Pharm. Pharmacol., 27, 547 (1975).

111.M. Nozaki and O. Hayaishi, in The Biology and Chemistry of Active Oxygen (Eds. J. V. Bannister and W. H. Bannister), Elsevier, New York, 1984, pp. 68 104.

112.D. R. Nelson, T. Kamataki, D. J. Waxman, F. P. Guengerich, R. W. Estabrook, R. Feyereisen,

F.J. Gonzales, M. J. Coon, I. C. Gunsalus, O. Gotoh, K. Okuda and D. W. Nebert, DNA Cell Biol., 12, 1 (1993).

113.A. Y. H. Lu and M. J. Coon, J. Biol. Chem., 243, 1331 (1968).

114.E. T. Morgan and M. J. Coon, Drug Metab. Dispos., 12, 358 (1984).

115.T. D. Porter and M. J. Coon, J. Biol. Chem., 258, 13469 (1991).

116.M. P. Lawton, J. R. Cashman, T. Cresteil, C. T. Dolphin, A. A. Elfarra, R. N. Hines, E. Hodgson,

T.Kimura, J. Ozols, I. R. Phillips, R. M. Philpot, L. L. Poulsen, A. E. Rettie, E. A. Shephard,

D.E. Williams and D. M. Ziegler, Arch. Biochem. Biophys., 308, 254 (1994).

117.J. R. Cashman, Chem. Res. Toxicol., 8, 165 (1995).

118.F. P. Guengerich, Crit. Rev. Biochem. Mol. Biol., 25, 97 (1990).

119.D. M. Ziegler, Annu. Rev. Pharmacol. Toxicol., 33, 179 (1993).

120.C. J. Parli and R. E. McMahon, Drug Metab. Dispos., 1, 337 (1973).

121.A. K. Cho, M. S. Maynard, R. M. Matsumoto, B. Lindeke, U. Paulsen and G. T. Miwa, Mol. Pharmacol., 22, 465 (1982).

122.A. H. Beckett and S. Al-Sarraj, J. Pharm. Pharmacol., 24, 174 (1972).

123.D. M. Ziegler, Drug Metab. Rev., 19, 1 (1988).

1662	Peter Hlavica and Michael Lehnerer

124.B. Clement, K. L. Lustig and D. M. Ziegler, Drug Metab. Dispos., 21, 24 (1993).

125.J. Lin, C. E. Berkman and J. Cashman, ISSX Proc., 8, 382 (1995).

126.J. Jonsson, R. C. Kammerer, G. Hallstrom,¨ B. Lindeke and A. K. Cho, in Biological Oxidation of Nitrogen (Ed. J. W. Gorrod), Elsevier, Amsterdam, 1978, pp. 25 29.

127.B. L. Møller and E. E. Conn, J. Biol. Chem., 254, 8575 (1979).

128.U. Paulsen-Sorman,¨ G. Lundkvist, A. H. Khuthier and B. Lindeke, Chem.-Biol. Interact., 47, 1 (1983).

129.R. T. Coutts and G. R. Jones, in Biological Oxidation of Nitrogen (Ed. J. W. Gorrod), Elsevier, Amsterdam, 1978, pp. 31 36.

130.R. T. Coutts, G. W. Dawson and A. H. Beckett, J. Pharm. Pharmacol., 28, 815 (1976).

131. A. H. Beckett, G. G. Gibson and K. Haya, in Biological Oxidation of Nitrogen (Ed.

J.W. Gorrod), Elsevier, Amsterdam, 1978, pp. 37 45.

132.J. W. Gorrod and N. J. Gooderham, in Microsomes, Drug Oxidations, and Drug Toxicity (Eds.

R.Sato and R. Kato), Japan Scientific Societies Press, Tokyo, 1982, pp. 565 566.

133.R. A. Prough, in Progress in Basic and Clinical Pharmacology, Vol. 1 (Eds. P. Lomax and

E. S. Vesell), Karger, Basel, 1988, pp. 103 131.

134.L. L. Poulsen, F. F. Kadlubar and D. M. Ziegler, Arch. Biochem. Biophys., 164, 774 (1974).

135.J. R. Cashman, Z. C. Yang and T. Hogberg, Chem. Res. Toxicol., 3, 428 (1990).

136.B. Lindeke, U. Paulsen and E. Anderson, Biochem. Pharmacol., 28, 3629 (1979).

137.M. Hirata, B. Lindeke and S. Orrenius, Biochem. Pharmacol., 28, 479 (1979).

138.P. R. Ortiz de Montellano and N. O. Reich, in Cytochrome P-450. Structure, Mechanism, and Biochemistry (Ed. P. R. Ortiz de Montellano), Plenum Press, New York, 1986, pp. 273 314.

139.M. Kiese and K. H. Plattig, Naunyn-Schmiedeberg’s Arch. Exp. Pathol. Pharmakol., 233, 484 (1958).

140.P. H. Morgan and A. H. Beckett, Tetrahedron, 31, 2595 (1975).

141.A. H. Beckett, G. E. Navas, A. J. Hutt and M. Farag, J. Pharm. Pharmacol., 31, 476 (1979).

142.A. K. Cho and J. M. Fukuto, in Progress in Basic and Clinical Pharmacology, Vol. 1 (Eds.

P. Lomax and E. S. Vesell), Karger, Basel, 1988, pp. 6 26.

143.K. L. Kaul and R. F. Novak, J. Pharmacol. Exp. Ther., 243, 384 (1987).

144.M. K. Trower, F. S. Sariaslani and F. G. Kitson, Biochem. Biophys. Res. Commun., 157, 1417 (1988).

145.A. R Hibberd and J. W. Gorrod, in Biological Oxidation of Nitrogen in Organic Molecules. Chemistry, Toxicology and Pharmacology (Eds. J. W. Gorrod and L.A. Damani), Ellis Horwood, Chichester, 1985, pp. 246 250.

146.L. A. Damani and P. A. Crooks, in Metabolic Basis of Detoxication: Metabolism of Functional Groups (Eds. W. B. Jacoby, J. R. Bend and J. Caldwell), Academic Press, New York, 1982, pp. 69 89.

147.S. P. Lam and J. W. Gorrod, in Biological Oxidation of Nitrogen in Organic Molecules (Eds. P. Hlavica and L. A. Damani), Gustav Fischer, Stuttgart, 1991, pp. 193 201.

148.J. W. Gorrod and S. P. Lam, in N-Oxidation of Drugs. Biochemistry, Pharmacology Toxicology

(Eds. P. Hlavica and L.A. Damani), Chapman and Hall, London, 1991, pp. 157 184.

149.C. Ioannides and D. V. Parke, Biochem. Pharmacol., 36, 4197 (1987).

150.J. W. Gorrod, in Biological Oxidation of Nitrogen in Organic Molecules. Chemistry, Toxicology and Pharmacology (Eds. J. W. Gorrod and L. A. Damani), Ellis Horwood, Chichester, 1985, pp. 219 230.

151.M. Hecker and V. Ullrich, Biochem. Pharmacol., 37, 3363 (1988).

152.J. Hes and L. A. Sternson, Drug Metab. Dispos., 2, 345 (1974).

153.L. A. Sternson and J. Hes, Pharmacology, 13, 234 (1975).

154.B. Clement, S. Schmitt and M. Zimmermann, Arch. Pharm., 324, 394 (1991).

155.F. F. Kadlubar and D. M. Ziegler, Arch. Biochem. Biophys., 162, 83 (1974).

156. L. A. Damani, in N-Oxidation of Drugs. Biochemistry, Pharmacology, Toxicology (Eds.

P. Hlavica and L. A. Damani), Chapman and Hall, London, 1991, pp. 239 261.

157.S. Chaykin and K. Bloch, Biochim. Biophys. Acta, 31, 213 (1959).

158.K. N. Murray and S. Chaykin, J. Biol. Chem., 241, 2029 (1966).

159.K. N. Murray and S. Chaykin, J. Biol. Chem., 241, 3468 (1966).

160.K. N. Murray, G. J. Watson and S. Chaykin, J. Biol. Chem., 241, 4798 (1966).

161.S. Kitamura and K. Tatsumi, Biochem. Biophys. Res. Commun., 120, 602 (1984).

162.S. Kitamura, Y. Wada and K. Tatsumi, Biochem. Biophys. Res. Commun., 125, 1117 (1984).

26. N-Oxidative transformations of CDN groups

1663

163.H. Tatsumi and O. Kanamitsu, J. Pharm. Soc. Jpn., 81, 1754 (1961).

164.G. M. J. Beijersbergen van Henegouwen, in N-Oxidation of Drugs. Biochemistry, Pharmacology, Toxicology (Eds. P.Hlavica and L. A. Damani), Chapman and Hall, London, 1991, pp. 455 473.

165.G. Stohrer¨ and G. B. Brown, J. Biol. Chem., 244, 2498 (1969).

166.G. B. Brown, Xenobiotica, 1, 361 (1971).

167.A. May, Enzymology, 18, 142 (1957).

168.T. Sakuragi and F. A. Kummerow, J. Org. Chem., 24, 1032 (1959).

169.H. Tatsumi and O. Kanamitsu, Yakugaku Zasshi, 81, 1767 (1961).

170.P. T. Sullivan, M. Kester and S. J. Norton, J. Med. Chem., 11, 1172 (1968).

171.A. H. Beckett and G. R. Jones, J. Pharm. Pharmacol., 29, 416 (1977).

172.R. T. Coutts, R. Dawe, G. W. Dawson and S. H. Kovach, Drug Metab. Dispos., 4, 35 (1976).

173.A. Jousserandot, J. L. Boucher, C. Desseaux, M. Delaforge and D. Mansuy, Bioorg. Med. Chem. Lett., 5, 423 (1995).

174.M. A. Marletta, J. Biol. Chem., 268, 12231 (1993).

175.J. L. Boucher, A. Genet, S. Vadon, M. Delaforge, Y. Henry and D. Mansuy, Biochem. Biophys. Res. Commun., 187, 880 (1992).

176.J. R. Vane, Proc. Roy. Soc. London, Ser. B, 343, 225 (1994).

177.J. Yoo and J. M. Fukuto, Biochem. Pharmacol., 50, 1995 (1995).

178.A. Raman and J. W. Gorrod, in Biological Oxidation of Nitrogen in Organic Molecules (Eds.

P.Hlavica and L. A. Damani), Gustav Fischer, Stuttgart, 1991, pp. 203 217.

179.E. G. DeMaster, F. N. Shirota and H. T. Nagasawa, J. Org. Chem., 57, 5074 (1992).

180.B. Clement, M. Immel, S. Schmitt and U. Steinmann, Arch. Pharm., 326, 807 (1993).

181.T. B. Gottlieb, R. C. Thomas and C. A. Chidsey, Clin. Pharmacol. Ther., 13, 436 (1972).

182.R. C. Thomas and H. Harpootlian, J. Pharm. Sci., 64, 1366 (1975).

183.G. A. Johnson, K. J. Barsuhn and J. M. McCall, Biochem. Pharmacol., 31, 2949 (1982).

184.R. M. Dawson, J. Appl. Toxicol., 14, 317 (1994).

185.I. B. Wilson, Fed. Proc., 18, 752 (1959).

186.E. J. Poziomek, B. E. Hackley and G. M. Steinberg, J. Org. Chem., 23, 714 (1958).

187.R. I. Ellin, Gen. Pharmacol., 13, 457 (1982).

188.L. P. A. de Jong and G. Z. Wolring, Biochem. Pharmacol., 29, 2379 (1980).

189.L. P. A. de Jong and G. Z. Wolring, Biochem. Pharmacol, 33, 1119 (1984).

190.J. G. Clement and P. A. Lockwood, Toxicol. Appl. Pharmacol., 64, 140 (1982).

191.J. G. Clement, Biochem. Pharmacol., 31, 1283 (1982).

192.J. Kassa, Pharmacol. Toxicol., 77, 382 (1995).

193.P. Eyer, I. Hagedorn, R. Klimmek, P. Lippstreu, M. Loffler,¨ H. Oldiges, U. Spohrer,¨ I. Steidl,

L.Szinicz and F. Worek, Arch. Toxicol., 66, 603 (1992).

194.J. H. Fleisher and L. W. Harris, Biochem. Pharmcol., 14, 641 (1965).

195.W. N. Aldridge, Croat. Chem. Acta, 47, 225 (1976).

196.D. M. Jerina, D. R. Boyd and J. W. Daly, Tetrahedron Lett., 6, 457 (1970).

197.J. S. Splitter and M. Calvin, J. Org. Chem., 30, 3427 (1965).

198.H. Pohlmann,¨ F. P. Theil, P. Franke and S. Pfeifer, Pharmazie, 41, 856 (1986).

199.G. M. J. Beijersbergen van Henegouwen, Arch. Toxicol., Suppl. 12, 3 (1988).

200.A. Bakri, G. M. J. Beijersbergen van Henegouwen and A. G. J. Sedee, Photochem. Photobiol., 44, 181 (1986).

201.G. M. J. Beijersbergen van Henegouwen, R. W. Busker, H. de Vries and S. A. Schoonderwoerd, Arch. Toxicol., Suppl. 12, 60 (1988).

202.E. Finkelstein, G. M. Rosen and E. J. Rauckman, Arch. Biochem. Biophys., 200, 1 (1980).

203.S. D. Aust, C. F. Chignell, T. M. Bray, B. Kalyanaraman and R. P. Mason, Toxicol. Appl. Pharmacol., 120, 168 (1993).

204.B. Kalyanaraman, Rev. Biochem. Toxicol., 4, 73 (1982).