Neur05c1ence • 8106ehav10ra1Rev1ew5. V01. 15. pp. 73-77. t~ Per9am0n 1:~e55p1e. 1991. Pr1nted1n the U.5.A.
0149-7634/91 $3.00 + .00
70x1c0k1net1c5 0f 50man: 5pec1e5 Var1at10n and 5tere05pec1f1c1ty 1n E11m1nat10n Pathway5 H E N D R 1 K P. 8 E N 5 C H 0 P
AND LE0
P. A. D E J 0 N 6
Pr1n5 Maur1t5 La60rat0r 3• 7 N 0 , P . 0 . 8 0 x 45 2280 AA, R1j5w1jk, 7he Nether1and5
8EN5CH0P, H. P. AND L. P. A. DE J 0 N 6 . 70x1c0k1net1c5 0f 50man: 5pec1e5 var1at10n and 5tere05pec1f1c10, 1n e11m1nat10n pathway5. NEUR05C1 8108EHAV REV 15(1 ) 73-77. 1991.-- 8100d 1eve15 0f the f0ur 5tere0150mer5 0f the nerve a9ent C( ---)P( ---)50man were ana1y2ed 9a5 chr0mat09raph1ca11y 1n anae5thet12ed, art1f1c1a11yre5p1rated and atr0p1n12ed rat5, 9u1nea p195 and marm05et5 at 1ntraven0u5 d05e5 0f C( • )P(•)-50man c0rre5p0nd1n9 w1th 1 ~ LD50. 7he re1at1ve1y n0nt0x1c C(---)P(+ )-150mer5 d15appear w1th1n a few m1nute5 fr0m the 6100d 5tream 0f a11 three 5pec1e5, wherea5 the 1eve15 0f the h19h1y t0x1c C(• )P( -)-150mer5 rema1n t0x1c01091ca11y re1evant f0r per10d5 0f 50-100 m1n 1n the three 5pec1e5 at d05e5 0f 2-3 LD50. E11m1nat10n pathway5 were 4uant1f1ed u51n9 t4C-1a6e1ed 50man 5tere0150mer5. Wherea5 the C( ---)P( + )-150mer5 are 1ar9e1y e11m1nated 6y way 0f en2ymat1c hydr01y515, the maj0r e11m1nat10n pathway f0r the C( • )P( - )-150mer5 15 61nd1n9 t0 var10u5 pr0te1n5, 1n c0mpet1t10n w1th 61nd1n9 t0 tar9et acety1ch011ne5tera5e. 1ntra5pec1e5 n0n11near1ty w1th d05e 1n the t0x1c0k1net1c5 0f the C( • )P( - )-150mer5 15 re1ated t0 heter09ene0u5 react1v1ty 0f the 61nd1n9 51te5. 1nter5pec1e5 n0n11near1ty 15 pr06a61y due t0 decrea51n9 am0unt5 0f 61nd1n9 51te5 1n the 0rder rat5 > 9u1nea p195 > pr1mate5. 1ead1n9 t0 1ncrea51n9 "•t0x1c0-ava11a6111ty•" 1n the rever5ed 0rder. 50man P1nac01y1methy1ph05ph0n0f1u0r1date 14C-C(• )P( + )-50man (1a6e1ed 1n P-CH 3 9r0up) 14C-C( • )P( - )-50man Nerve a9ent 5tere0150mer5 70x1c0k1net1c5 Rat 6u1nea p19 L1near1ty w1th d05e Hydr01y515 8 1 n d 1 n 9 5tere05pec1f1c1ty
Marm05et
6). 5u65e4uent 5tud1e5 5h0wed that the C( --- )P( - )-150mer5 0f 50man 1nh161t AChE fr0m var10u5 50urce5 w1th rate c0n5tant5 that are appr0x1mate1y f0ur 0rder5 0f ma9n1tude h19her than th05e 0f the C( -+ ) P ( + )-150mer5 (3,6). 5tere05e1ect1ve ant1ch011ne5tera5e act1v1t1e5 are ref1ected 1n d1fference5 1n t0x1c1ty. 7 h e LD50 (m1ce, 5u6cutane0u51y) 0 f the C( --- )P( + )-150mer5 15 > 2 m9/k9, wherea5 /.he c0rre5p0nd1n9 va1ue f0r the C( + - ) P ( - )-150mer5 15 8 pM wh1ch 15 we11 6e10w the 1eve1 0f t0x1c01091ca1 519n1f1cance and 2) 4uant1fy the maj0r e11m1nat10n pathway5 0f the 150mer5, 1.e., en2ymat1c hydr01y515 and c0va1ent 61nd1n9 t0 pr0te1n5.7he u5e 0f the5e meth0d5 at 1ntraven0u5 d05e5 0f C( ••. )P( • )-50man c0rre5p0nd1n9 t0 1-6 LD50 c1ar1f1ed 5evera1 a5pect5 0f 1nter5pec1e5 d1fference5 1n rat5, 9u1nea p195 and marm05et5, e5pec1a11y w1th re9ard t0 1) extreme d1fference5 1n the per515tence 0f the var10u5 50man 150mer5, 2) (n0n) 11near1ty w1th d05e, and 3) c0n5e4uence5 0f the5e d1fference5 f0r treatment 0f 50man 1nt0x1cat10n. 1n 5p1te 0f 06v10u5 9ap5 1n 0ur t0x1c0k1net1c 5tud1e5, we 6e11eve t0 have 06ta1ned a f1rm 4uant1tat1ve 6a515 f0r further w0rk 0n 50man 1nt0x1cat10n. Pre5ent1y, the t0x1c0k1net1c data are 6e1n9 u5ed 1n 0ur 1a60rat0ry t0 1mpr0ve pretreatment 0f 50man 1nt0x1cat10n w1th ta110r-made ant1ch011ne5tera5e5 (13). 7 h e 1nve5t19at10n5 a1m at a part1a1 pr0tect10n 0f AChE 0ffered 6y the5e c0mp0und5 that keep5 pace w1th the 9radua1 dec11ne 0f the c0ncentrat10n5 0f the t0x1c C( • )P( - )-50man 150mer5. ACKN0wLED6EMEN75 An1ma1 exper1ment5 were perf0rmed under re5p0n516111ty0f Dr5. 0. L. W01thu15 and H.P.M. Van He1den, Med1ca1 8101091ca1 La60rat0ry
7A8LE 5 RAD10ME7R1CALLY DE7ERM1NED 57ERE05PEC1F1C17Y 0F 1N v1v0 c0vALEN7 81ND1N6 AND HYDR0LY515 1N 6U1NEA P165 1 H AF7ER 1N7RAvEN0u5 ADM1N157RA710N0F 6 LD50 0F C( + )P( • 1-50MAN REc0N5717u7ED FR0M ~4C-C(• )P( - )-50MAN AND EQU1M0LAR UNLA8ELED c( ---)P( + )-50MAN. 0R v1cE vER5A. PERCEN7A6E5 0F 707AL REC0vERY* Hydr01y515 7155ue 14C-C(••.)P(-) P1a5ma Lun9 L1ver 8ra1n
23 54 10 31
C0va1ent 81nd1n9
1aC-C(•)P(+)t4C-C(•••)P(-) 58 82 52 75
*Mean va1ue5 fr0m 5 mea5urement5.
73 47 84 70
14C-C(--)P(+) 39 16 45 25
5PEC1E5 V A R 1 A 7 1 0 N 1N 5 0 M A N 7 0 X 1 C 0 K 1 N E 7 1 C 5
77
7 N 0 , and 0f Dr. J. P. Lan9en6er9, Pr1n5 Maur1t5 La60rat0ry 7 N 0 . We are 9ratefu1 t0 Er1k 81j1eve1d, Mr5. Anne Due, Henk 7rap, Dav1d 8erh1t0e and Mr5. C0rry Van D1jk f0r techn1ca1 a5515tance. 24C( -- )P( -+-)-50man wa5 k1nd1y d0nated 6y Dr. Dav1d E. Len2, U.5. Army Med1ca1
Re5earch 1n5t1tute 0f Chem1ca1 Defen5e, A6erdeen Pr0v1n9 6r0und, MD, U5A, and 6y Mme. 15a6e11e Ca11e6at, Centre d•Etude5 du 80uchet, Vert1e-Pet1t, France.
REFERENCE5 1. 8en5ch0p, H. P.; 81j1eve1d, E. C.; De J0n9, L. P. A.; Van der W1e1, H. J.; Van He1den, H. P. M. 70x1c0k1net1c5 0f the f0ur 5tere0150mer5 0f the nerve a9ent 50man 1n atr0p1n12ed rat5--1nf1uence 0f a 50man 51mu1at0r. 70x1c01. App1. Pharmac01. 90:490-500; 1987. 2. 8en5ch0p, H. P.; 81j1eve1d, E. C.; 0tt0, M. F.; De9enhardt, C. E. A. M.; Van He1den, H. P. M.; De J0n9, L. P. A. 5ta61112at10n and 9a5 chr0mat09raph1c ana1y515 0f the f0ur 5tere0150mer5 0f 1,2,2-tr1methy1pr0py1 methy1ph05ph0n0f1u0r1date (50man) 1n rat 6100d. Ana1. 810chem. 151:242-253; 1985. 3. 8en5ch0p, H. P.; De J0n9, L. P. A. Nerve a9ent 5tere0150mer5: Ana1y515, 1501at10n, and t0x1c0109y. Acc. Chem. Re5. 21:368-374; 1988. 4. 8en5ch0p, H. P.; De J0n9, L. P. A. Unpu6115hed 065ervat10n5. 5. 8en5ch0p, H. P.; K0n1n95, C. A. 6.; De J0n9, L. P. A. 6a5 chr0mat09raph1c 5eparat10n and 1dent1f1cat10n0f the f0ur 5tere0150mer5 0f 0-1,2,2-tr1methy1pr0py1 methy1ph05ph0n0f1u0r1date (50man). 5tere05pec1f1c1ty 0f 1n v1tr0 "det0x1f1cat10n•• react10n5. J. Am. Chem. 50c. 103:4260--4262; 1981. 6. 8en5ch0p, H. P.; K0n1n95, C. A. 6.; Van 6enderen, J.; De J0n9, L. P. A. 1501at10n, ant1ch011ne5tera5e pr0pert1e5, and acute t0x1c1ty 1n m1ce 0f the f0ur 5tere0150mer5 0f the nerve a9ent 50man. 70x1c01. App1. Pharmac01. 72:61-74; 1984. 7. C1ement, J. 6 . ; 8en5ch0p, H. P.; De J0n9, L. P. A.; W01thu15, 0 . L. 5tere0150mer5 0f 50man (p1nac01y1 methy1ph05ph0n0f1u0r1date): 1nh161t10n 0f 5erum car60xy11c e5ter hydr01a5e and p0tent1at10n 0f the1r t0x1c1ty 6y C8DP [2-(2-methy1phen0xy)-4H-1,3,2-6en20d10xaph05ph0r1n-2-0x1de] 1n m1ce. 70x1c01. App1. Pharmac01.89:141-143; 1987. 8. De J0n9, L. P. A.; Van D1jk, C.; 8en5ch0p, H. P. Hydr01y515 0fthe
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f0ur 5tere0150mer5 0f 50man cata1y2ed 6y 11ver h0m09enate and p1a5ma fr0m rat, 9u1nea p19 and marm05et, and 6y human p1a5ma. 810chem. Pharmac01. 37:2939-2948; 1988. F1e15her, J. H.; Harr15, L. W. Dea1ky1at10n a5 a mechan15m f0r a9e1n9 0f ch011ne5tera5e after p0150n1n9 w1th p1nac01y1 methy1ph05ph0n0f1u0r1date. 810chem. Pharmac01. 14:641~50; 1965. 6earhardt, J. M.; Jep50n, 6 . W.; C1ewe11, H. J., 111; Ander5en, M. E.; C0n011y, R. 8. Phy5101091ca11y6a5ed pharmac0k1net1c and pharmac0dynam1c m0de1 f0r the 1nh161t10n 0f acety1ch011ne5tera5e 6y d1150pr0py1 f1u0r0ph05phate. 70x1c01. App1. Pharmac01. 106:295-310; 1990. Harr15, L. W.; 8ra5we11, L. M.; F1e15her, J. H.; C11ff, W. J. Meta6011te5 0f p1nac01y1 methy1ph05ph0n0f1u0r1date (50man) after en2ymat1c hydr01y515 1n v1tr0. 810chem. Pharmac01. 13:1129-1136; 1964. H01m5tedt, 8., ed. Pr0ceed1n95 0f the th1rd 5ymp051um 0n pr0phy1ax15 and treatment 0f chem1ca1 p0150n1n9, Apr11 22-24, 1985, 5t0ckh01m. Fundam. App1. 70x1c01. 5(6):part 2; 1985. Lan9en6er9, J. P.; De J0n9, L. P. A.; 0tt0, M. F.; 8en5ch0p, H. P. 5p0ntane0u5 and 0x1me-1nduced react1vat10n 0f acety1ch011ne5tera5e 1nh161ted 6y ph05ph0ram1date5. Arch. 70x1c01. 62:305-310; 1988. Maxwe11, D. M.; 8recht, K. M.; 0•Ne111, 8. L. 7he effect 0f car60xy1e5tera5e 1nh161t10n0n 1nter5pec1e5 d1fference5 1n 50man t0x1c1ty. 70x1c01. Lett. 39:35-42; 1987. Maxwe11, D. M.; Len2, D. E.; 6r0ff, W. A.; Kam1n5k15, A.; Fr0eh11ch, H. L. 7he effect5 0f 6100d f10w and det0x1f1cat10n 0n 1n v1v0 ch011ne5tera5e 1nh161t10n 6y 50man 1n rat5. 70x1c01. App1. Pharmac01. 88:66--76; 1987. W01thu15, 0. L.; 8erend5, F.; Meeter, E. Pr061em5 1n the therapy 0f 50man p0150n1n9. Fundam. App1. 70x1c01. 1:183-192; 1981.
0149-7634/91 $3.00 + .00
70x1c0k1net1c5 0f 50man: 5pec1e5 Var1at10n and 5tere05pec1f1c1ty 1n E11m1nat10n Pathway5 H E N D R 1 K P. 8 E N 5 C H 0 P
AND LE0
P. A. D E J 0 N 6
Pr1n5 Maur1t5 La60rat0r 3• 7 N 0 , P . 0 . 8 0 x 45 2280 AA, R1j5w1jk, 7he Nether1and5
8EN5CH0P, H. P. AND L. P. A. DE J 0 N 6 . 70x1c0k1net1c5 0f 50man: 5pec1e5 var1at10n and 5tere05pec1f1c10, 1n e11m1nat10n pathway5. NEUR05C1 8108EHAV REV 15(1 ) 73-77. 1991.-- 8100d 1eve15 0f the f0ur 5tere0150mer5 0f the nerve a9ent C( ---)P( ---)50man were ana1y2ed 9a5 chr0mat09raph1ca11y 1n anae5thet12ed, art1f1c1a11yre5p1rated and atr0p1n12ed rat5, 9u1nea p195 and marm05et5 at 1ntraven0u5 d05e5 0f C( • )P(•)-50man c0rre5p0nd1n9 w1th 1 ~ LD50. 7he re1at1ve1y n0nt0x1c C(---)P(+ )-150mer5 d15appear w1th1n a few m1nute5 fr0m the 6100d 5tream 0f a11 three 5pec1e5, wherea5 the 1eve15 0f the h19h1y t0x1c C(• )P( -)-150mer5 rema1n t0x1c01091ca11y re1evant f0r per10d5 0f 50-100 m1n 1n the three 5pec1e5 at d05e5 0f 2-3 LD50. E11m1nat10n pathway5 were 4uant1f1ed u51n9 t4C-1a6e1ed 50man 5tere0150mer5. Wherea5 the C( ---)P( + )-150mer5 are 1ar9e1y e11m1nated 6y way 0f en2ymat1c hydr01y515, the maj0r e11m1nat10n pathway f0r the C( • )P( - )-150mer5 15 61nd1n9 t0 var10u5 pr0te1n5, 1n c0mpet1t10n w1th 61nd1n9 t0 tar9et acety1ch011ne5tera5e. 1ntra5pec1e5 n0n11near1ty w1th d05e 1n the t0x1c0k1net1c5 0f the C( • )P( - )-150mer5 15 re1ated t0 heter09ene0u5 react1v1ty 0f the 61nd1n9 51te5. 1nter5pec1e5 n0n11near1ty 15 pr06a61y due t0 decrea51n9 am0unt5 0f 61nd1n9 51te5 1n the 0rder rat5 > 9u1nea p195 > pr1mate5. 1ead1n9 t0 1ncrea51n9 "•t0x1c0-ava11a6111ty•" 1n the rever5ed 0rder. 50man P1nac01y1methy1ph05ph0n0f1u0r1date 14C-C(• )P( + )-50man (1a6e1ed 1n P-CH 3 9r0up) 14C-C( • )P( - )-50man Nerve a9ent 5tere0150mer5 70x1c0k1net1c5 Rat 6u1nea p19 L1near1ty w1th d05e Hydr01y515 8 1 n d 1 n 9 5tere05pec1f1c1ty
Marm05et
6). 5u65e4uent 5tud1e5 5h0wed that the C( --- )P( - )-150mer5 0f 50man 1nh161t AChE fr0m var10u5 50urce5 w1th rate c0n5tant5 that are appr0x1mate1y f0ur 0rder5 0f ma9n1tude h19her than th05e 0f the C( -+ ) P ( + )-150mer5 (3,6). 5tere05e1ect1ve ant1ch011ne5tera5e act1v1t1e5 are ref1ected 1n d1fference5 1n t0x1c1ty. 7 h e LD50 (m1ce, 5u6cutane0u51y) 0 f the C( --- )P( + )-150mer5 15 > 2 m9/k9, wherea5 /.he c0rre5p0nd1n9 va1ue f0r the C( + - ) P ( - )-150mer5 15 8 pM wh1ch 15 we11 6e10w the 1eve1 0f t0x1c01091ca1 519n1f1cance and 2) 4uant1fy the maj0r e11m1nat10n pathway5 0f the 150mer5, 1.e., en2ymat1c hydr01y515 and c0va1ent 61nd1n9 t0 pr0te1n5.7he u5e 0f the5e meth0d5 at 1ntraven0u5 d05e5 0f C( ••. )P( • )-50man c0rre5p0nd1n9 t0 1-6 LD50 c1ar1f1ed 5evera1 a5pect5 0f 1nter5pec1e5 d1fference5 1n rat5, 9u1nea p195 and marm05et5, e5pec1a11y w1th re9ard t0 1) extreme d1fference5 1n the per515tence 0f the var10u5 50man 150mer5, 2) (n0n) 11near1ty w1th d05e, and 3) c0n5e4uence5 0f the5e d1fference5 f0r treatment 0f 50man 1nt0x1cat10n. 1n 5p1te 0f 06v10u5 9ap5 1n 0ur t0x1c0k1net1c 5tud1e5, we 6e11eve t0 have 06ta1ned a f1rm 4uant1tat1ve 6a515 f0r further w0rk 0n 50man 1nt0x1cat10n. Pre5ent1y, the t0x1c0k1net1c data are 6e1n9 u5ed 1n 0ur 1a60rat0ry t0 1mpr0ve pretreatment 0f 50man 1nt0x1cat10n w1th ta110r-made ant1ch011ne5tera5e5 (13). 7 h e 1nve5t19at10n5 a1m at a part1a1 pr0tect10n 0f AChE 0ffered 6y the5e c0mp0und5 that keep5 pace w1th the 9radua1 dec11ne 0f the c0ncentrat10n5 0f the t0x1c C( • )P( - )-50man 150mer5. ACKN0wLED6EMEN75 An1ma1 exper1ment5 were perf0rmed under re5p0n516111ty0f Dr5. 0. L. W01thu15 and H.P.M. Van He1den, Med1ca1 8101091ca1 La60rat0ry
7A8LE 5 RAD10ME7R1CALLY DE7ERM1NED 57ERE05PEC1F1C17Y 0F 1N v1v0 c0vALEN7 81ND1N6 AND HYDR0LY515 1N 6U1NEA P165 1 H AF7ER 1N7RAvEN0u5 ADM1N157RA710N0F 6 LD50 0F C( + )P( • 1-50MAN REc0N5717u7ED FR0M ~4C-C(• )P( - )-50MAN AND EQU1M0LAR UNLA8ELED c( ---)P( + )-50MAN. 0R v1cE vER5A. PERCEN7A6E5 0F 707AL REC0vERY* Hydr01y515 7155ue 14C-C(••.)P(-) P1a5ma Lun9 L1ver 8ra1n
23 54 10 31
C0va1ent 81nd1n9
1aC-C(•)P(+)t4C-C(•••)P(-) 58 82 52 75
*Mean va1ue5 fr0m 5 mea5urement5.
73 47 84 70
14C-C(--)P(+) 39 16 45 25
5PEC1E5 V A R 1 A 7 1 0 N 1N 5 0 M A N 7 0 X 1 C 0 K 1 N E 7 1 C 5
77
7 N 0 , and 0f Dr. J. P. Lan9en6er9, Pr1n5 Maur1t5 La60rat0ry 7 N 0 . We are 9ratefu1 t0 Er1k 81j1eve1d, Mr5. Anne Due, Henk 7rap, Dav1d 8erh1t0e and Mr5. C0rry Van D1jk f0r techn1ca1 a5515tance. 24C( -- )P( -+-)-50man wa5 k1nd1y d0nated 6y Dr. Dav1d E. Len2, U.5. Army Med1ca1
Re5earch 1n5t1tute 0f Chem1ca1 Defen5e, A6erdeen Pr0v1n9 6r0und, MD, U5A, and 6y Mme. 15a6e11e Ca11e6at, Centre d•Etude5 du 80uchet, Vert1e-Pet1t, France.
REFERENCE5 1. 8en5ch0p, H. P.; 81j1eve1d, E. C.; De J0n9, L. P. A.; Van der W1e1, H. J.; Van He1den, H. P. M. 70x1c0k1net1c5 0f the f0ur 5tere0150mer5 0f the nerve a9ent 50man 1n atr0p1n12ed rat5--1nf1uence 0f a 50man 51mu1at0r. 70x1c01. App1. Pharmac01. 90:490-500; 1987. 2. 8en5ch0p, H. P.; 81j1eve1d, E. C.; 0tt0, M. F.; De9enhardt, C. E. A. M.; Van He1den, H. P. M.; De J0n9, L. P. A. 5ta61112at10n and 9a5 chr0mat09raph1c ana1y515 0f the f0ur 5tere0150mer5 0f 1,2,2-tr1methy1pr0py1 methy1ph05ph0n0f1u0r1date (50man) 1n rat 6100d. Ana1. 810chem. 151:242-253; 1985. 3. 8en5ch0p, H. P.; De J0n9, L. P. A. Nerve a9ent 5tere0150mer5: Ana1y515, 1501at10n, and t0x1c0109y. Acc. Chem. Re5. 21:368-374; 1988. 4. 8en5ch0p, H. P.; De J0n9, L. P. A. Unpu6115hed 065ervat10n5. 5. 8en5ch0p, H. P.; K0n1n95, C. A. 6.; De J0n9, L. P. A. 6a5 chr0mat09raph1c 5eparat10n and 1dent1f1cat10n0f the f0ur 5tere0150mer5 0f 0-1,2,2-tr1methy1pr0py1 methy1ph05ph0n0f1u0r1date (50man). 5tere05pec1f1c1ty 0f 1n v1tr0 "det0x1f1cat10n•• react10n5. J. Am. Chem. 50c. 103:4260--4262; 1981. 6. 8en5ch0p, H. P.; K0n1n95, C. A. 6.; Van 6enderen, J.; De J0n9, L. P. A. 1501at10n, ant1ch011ne5tera5e pr0pert1e5, and acute t0x1c1ty 1n m1ce 0f the f0ur 5tere0150mer5 0f the nerve a9ent 50man. 70x1c01. App1. Pharmac01. 72:61-74; 1984. 7. C1ement, J. 6 . ; 8en5ch0p, H. P.; De J0n9, L. P. A.; W01thu15, 0 . L. 5tere0150mer5 0f 50man (p1nac01y1 methy1ph05ph0n0f1u0r1date): 1nh161t10n 0f 5erum car60xy11c e5ter hydr01a5e and p0tent1at10n 0f the1r t0x1c1ty 6y C8DP [2-(2-methy1phen0xy)-4H-1,3,2-6en20d10xaph05ph0r1n-2-0x1de] 1n m1ce. 70x1c01. App1. Pharmac01.89:141-143; 1987. 8. De J0n9, L. P. A.; Van D1jk, C.; 8en5ch0p, H. P. Hydr01y515 0fthe
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