PROGRAM: MODEL FOR LIPID PEROXIDATION IN LIVER SLICES in vitro ' ******* LPOXLIV.CSL ******* ' ' ******* PART 1 0F 2 OF MODEL LPOXLIV ******* ' '-------------------------------------------------------------------' 'SIMULATE PRODUCTION OF TBARS FROM PUFA IN LIVER SLICES in vitro ' 'BBPD MODEL FOR CHEMICALLY INDUCED LIPID PEROXIDATION IN LIVER ' 'SLICES in vitro ' 'Originally posted at PBPK-L Source Code Listing, ' 'URL: http://www.navy.al.wpafb.af.mil/new.htm ' 'DISCLAIMER: By using this PBPK source code you, the user, ' ' implicitly agrees with the conditions and rules stated in this ' ' source code disclaimer. If you have not read ' ' this yet, please read it now. If you do not agree with the ' ' conditions and rules stated in it, please dispose of all contents ' ' of the PBPK source file and all related files now in your ' ' possession. The PBPK computer modeling programs are placed here by' ' their authors for the convenience of others interested in PBPK ' ' modeling. No representation of their suitability or correctness is' ' implied. Please understand that PBPK models are complex entities ' ' whose value is minimal when taken out of context. With that ' ' understanding, you are welcome to use this code for teaching and ' ' further development of the ideas that they represent. The ' ' information and/or opinions presented here are those of the ' ' authors and are not endorsed by the US Air Force, US Navy, US ' ' Army, Tri-Service Toxicology Consortium, Department of Defense, or' ' the US Government. The US Air Force, US Navy, US Army, Tri-Service' ' Toxicology Consortium, Department of Defense, or the US Government' ' and the authors of this PBPK source code accept no responsibility ' ' for damages resulting from the use of the code and make no ' ' warranty or representation, either express or implied, including ' ' but not limited to, any implied warranty of merchantability or ' ' fitness for a particular purpose. PBPK source code is provided *as' ' is*, and you, its user, assume all risks when using it. ' ' Description of this program has been published: Byczkowski,J.Z., ' ' Channel,S.R., Pravecek,T.L., and Miller,C.R. (1996) ' ' Mathematical model for chemically induced lipid peroxidation in ' ' precision-cut liver slices: Computer simulation and experimental ' ' calibration. Computer Methods Progr. Biomed. 50, 73-84. ' ' Reprints of his article are indicated as AL/OE-TR-1996-0081 by ' ' Armstrong Aerospace Medical Research Laboratory, Wright Patterson ' ' Air Force Base, OH. ' ' Results of simulation and experimental details have been ' ' published: Byczkowski,J.Z., Channel,S.R., and Pravecek.L. (1995). ' ' Development and experimental calibration of the mathematical ' ' model for lipid peroxidation in mouse liver slices. Reprints of ' ' this article are indicated as Technical Report, AL/OE-TR-1995-0179' ' by Armstrong Aerospace Medical Research Laboratory, Wright ' ' Patterson Air Force Base, OH. ' 'Key words: Biologically based pharmacodynamic model, BBPD, Liver ' ' in vitro, Lipid peroxidation, Toxicology, tert-Butyl ' ' hydroperoxide, Bromotrichloromethane, Mouse, Rat. ' ' Please send comments to the authors E-mail address: ' ' JANUSZ.BYCZKOWSKI@USA.NET ' '^^^^^^^^^^^^^^^Please do not delete this message^^^^^^^^^^^^^^^^^^^' '-------------------------------------------------------------------' 'THE PURPOSE OF THIS PROGRAM IS TO SIMULATE PRODUCTION OF TBARS' 'FROM PUFA IN LIVER SLICES in vitro. ' INITIAL 'DEFAULT PEROXIDATION PARAMETERS FOR LIVER, ESTIMATED FROM ' 'Tappel et al. (1989) Free Radical Biol. Med. 7: 361-368 ' '[per 0.1 g of liver] ' CONSTANT IND1 = 5.0 $'inducer 1 [mcM /0.1g liv] ' CONSTANT PUF = 7.0 $'[microMol/0.1 g liver] ' CONSTANT PXZLUF= 12.0 $'peroxidizability of PUFA L[1/h]' CONSTANT PXZHUF= 24.0 $'peroxidizability of PUFA H[1/h]' CONSTANT ANOX1 = 0.005 $'Vit.E antiox[microMol/0.1g liv]' CONSTANT ACT1 = 0.0003 $'activator1[mcM cytP450/0.1gliv]' CONSTANT GSH = 0.6 $'glutathione [mcroM/0.1 g liver]' CONSTANT PXTTBA= 0.1 $'yield ofTBARS/Mol hydroperoxide' CONSTANT LPUF = 3. $'LA-derivative PUFA[mcMol/0.1 g]' CONSTANT HPUF = 4. $'HA-derivative PUFA[mcMol/0.1 g]' CONSTANT ANOX2 = 0. $'non-Vit.E antiox[mcM/0.1 g liv]' CONSTANT ANOX3 = 0. $'added antioxidant[mcM/0.1g liv]' CONSTANT EFANO1 = 1. $'effectiveness of Vit.E ' CONSTANT EFANO2 = 0. $'effectiveness of non-Vit.E a-o ' CONSTANT EFANO3 = 0. $'effectiveness of added a-o ' CONSTANT ANOXUF = 2. $'antioxidant use factor [/mcmol]' CONSTANT ACT2 = 0. $'activator 2 [mcM/0.1 g liver] ' CONSTANT ACACT1 = 1. $'activity of activator 1 ' CONSTANT ACACT2 = 0. $'activity of activator 2 ' CONSTANT ACTDGF = 1.5 $'activator degradation fctr /mcm' CONSTANT IND2 = 0. $'inducer2[mcM chemical/0.1g liv]' CONSTANT PTIND1 = 4.1 $'potency of inducer 1 [1/mcmol] ' CONSTANT PTIND2 = 0. $'potency of inducer 2 [1/mcmol] ' CONSTANT INDLF = 0.1200 $'inducer loss factor [1/h] ' CONSTANT PXRATE = 0.00029 $'peroxidation rate [mcm/mcm] ' CONSTANT AUTOXF = 0.00012 $'autooxidation factor [1/h] ' CONSTANT GPENZA = 1. $'glutathione peroxidase[/mcM] ' CONSTANT PXREDF = 0.017 $'hydroperoxide reduction fctr /h' CONSTANT PHYSPX = 0. $'physiological levels of Hperox ' CONSTANT ANREG = 0. $'antioxidant regenerated in vivo' CONSTANT BCKGD = 0.0 $'TBARS in control [mcm/0.1 g] ' CONSTANT TSTOP = 2. $'end of simulation [h] ' 'TIMING COMMANDS ' CONSTANT POINTS = 500. CINT=TSTOP/POINTS $'communication interval ' ' INITIALIZATION ' 'RESETS INITIAL CONDITIONS BEFORE PEROXIDATION ' CONSTANT ACTLOS=0. $'activator loss ' CONSTANT AUTOX =0. $'autooxidation ' CONSTANT PXREDG=0. $'Hperoxides red. by GSH peroxidase' CONSTANT PXLUF =0.00199 $'L-Hydroperoxides formed ' CONSTANT PXHUF =0.0053 $'H-Hydroperoxides formed ' CONSTANT PXREM =0. $'accumulated remaining Hperoxides ' CONSTANT TPX =0. $'accumlted total Hperoxides formed' CONSTANT AUTOXA=0. $'no autooxidation ' CONSTANT PXREDA=0. $'no reduced Hperoxides ' CONSTANT PXHUFA=0. $'no Hperoxides from H-PUFA ' CONSTANT PXLUFA=0. $'no Hperoxides from L-PUFA ' CONSTANT ILR =0. $'rate of inducer loss = 0. ' CONSTANT INDLOS=0. $'no inducer lost ' END $'End of Initial ' DYNAMIC ALGORITHM IALG = 2 $'Gear stiff method ' DERIVATIVE PROCEDURAL IF (LPUFRE.LE.0) LPUFRE = 0. IF (HPUFRE.LE.0) HPUFRE = 0. IF (ACTLOS.GE.ACTEF) ACTLOS = ACTEF IF (ANOXRE.LE.1.e-10) ANOXRE = 1.e-10 IF (GSHREM.LE.0) GSHREM = 0. IF (INDLOS.GE.INDEF) INDLOS = INDEF IF (PXREDA.GE.TPX) PXREDA = TPX END $'End of procedural ' ' Amounts of remaining polyunsaturated fatty acids ' LPUFRE = LPUF - PXLUFA - AUTOXA/2 HPUFRE = HPUF - PXHUFA - AUTOXA/2 ' Amount of effective activator ' ACTEF = ACT1*ACACT1 + ACT2*ACACT2 ' Activator loss ' ACTLOS = ACTEF*ACTDGF*TPX ' Amount of remaining activator ' ACTREM = ACTEF - ACTLOS ' Amount of effective inducer ' INDEF = IND1*PTIND1 + IND2*PTIND2 ' Amount of remaining inducer ' INDREM = INDEF - INDLOS ' Inducer loss rate ' ILR = INDEF*INDLF ' Amount of activated inducer ' ACTIND = INDREM*ACTREM ' Amount of effective antioxidant ' ANOXEF = ANOX1*EFANO1 + ANOX2*EFANO2 + ANOX3*EFANO3 ' Amount of remaining antioxidant ' ANOXRE = ANOXEF - ANOXEF*TPX*ANOXUF + ANREG ' Rate of hydroperoxides formation by action of activated ' ' inducer on PUFA ' PXLUF = LPUFRE*PXZLUF*ACTIND*PXRATE/ANOXRE PXHUF = HPUFRE*PXZHUF*ACTIND*PXRATE/ANOXRE ' Rate of autooxidation ' AUTOX = (LPUFRE + HPUFRE)*AUTOXF*TPX/ANOXRE ' Amount of accumulated total hydroperoxides formed ' TPX = AUTOXA + PXLUFA + PXHUFA + PHYSPX ' Amount of remaining glutathione ' GSHREM = GSH - PXREDA ' Rate of hydroperoxides reduced by glutathione peroxidase ' PXREDG = PXREM*GPENZA*GSHREM*PXREDF ' Amount of accumulated remaining hydroperoxides ' PXREM = TPX - PXREDA ' Amount of TBARS from accumulated remaining hydroperoxides ' TBARS = PXREM*PXTTBA + BCKGD ' Inducer loss ' INDLOS = INTEG(ILR,0.) ' Amount of accumulated hydroperoxides formed by action of ' ' activated inducer on PUFA ' PXLUFA = INTEG(PXLUF, 0.) PXHUFA = INTEG(PXHUF, 0.) ' Amount of accumulated autooxidation ' AUTOXA = INTEG(AUTOX, 0.) ' Amount of accumulated hydroperoxides reduced by glutathione' ' peroxidase ' PXREDA = INTEG(PXREDG, 0.) TERMT(T.GE.TSTOP) $'Termination at TSTOP ' END $'End of derivative ' END $'End of dynamic ' '^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^' TERMINAL $'Resets parameters to initial values' ACTREM = ACTEF INDREM = INDEF ANOXRE = ANOXEF END $'End of terminal ' '^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^' END $'End of program ' 'CUT HERE>----------------------------------------------------------' ' ***** END OF PART 1 0F 2 OF MODEL LPOXLIV***** '