TABLE 1

Tissue distribution of rat enzymes involved in prodrug activation

Liver Kidney Intestine Brain Lung Adrenal Testis Skin Spleen Heart Serum Stomach Lymph node Muscle
Aldehyde oxidasea ++ (4.0) + (1.4) + (1.3) ++ (-) ++ (0.4) ND (-) + (-) + (-) ND (0.6) ± ND - (-) + (-) - (-) ND (-)
Amino acid oxidaseb
l-AAO
d-AAO (16.2) (17.1) (-) (21.5) () (-) (-) (-) (-) (ND) (ND) (-) (-) (-)
Cytochrome P450c 0.22-0.92 0.05-0.21 0.02-0.13 0.025-0.051 0.035 0.50 0.05-0.10 0.05 0.025 - - - - -
P450 reductased 37.1 25.1 47.4 6.1 16.4 53.1 7.1 - - - - - - -
DT-diaphorasee 389 28 76 - 117 - - - - - - - - -
Thymidylate synthasef 0.18 0.07 0.04 0.11 0.39 - 1.42 - 3.32 0.14 - - - ND
Thymidine phosphorylaseg 14 2.3 25 - - - - - ND - - - - -
Glutathione S-transferaseh
Cytosolic 1400 336 429 190 79 253 3850 - 56 93 - - - -
Microsomal 126 8.5 60 7.9 15 52 129 - 9 7.2 - - - -
Deoxycytidine kinasei 0.032 - - - - - - - 0.091 - - - -
Cysteine conjugate β-lyasej 2.2 23.0 0.6 0.8 0.2 - - - 0.7 0.9 - - - -
• ND, no detectable enzyme activity or no staining observed; -, no data available.

• a Based on immunohistochemical staining. ±, equivocal staining; +, low staining; ++, moderate staining (Moriwaki et al., 1996). Values in parentheses indicate specific activities in guinea pig tissues expressed as nmol/min/mg of protein with phthalazine (Beedham et al., 1987). Intestine value represents sum of ileum, jejunum, and duodenum (Beedham et al., 1987).

• b Expressed as μmol/min/mg of protein with d-alanine as a substrate in hog tissues (Katagiri et al., 1991). In lung tissue the enzyme was detected with an enzyme immunoassay; however, enzyme activity could not be determined.

• c Expressed as nmol/mg of microsomal protein (Vainio, 1980).

• d Expressed as nmol/min/mg of protein with cytochrome c as a substrate (Benedetto et al., 1976).

• e Expressed as nmol/min/mg of protein with menadione as a substrate (Schlager and Powis, 1990).

• f Expressed as nmol/h/mg of protein with dUMP as a substrate (Hashimoto et al., 1988). High activities were observed in thymus (11.33) and bone marrow (2.70).

• g Expressed as μmol/h/g of tissue with thymidine as a substrate (Zimmerman and Seidenberg, 1964).

• h Expressed as nmol/min/mg of protein with 1-chloro-2,4-dinitrobenzene (CDNB) as a substrate (DePierre and Morgenstern, 1983).

• i Expressed as pmol/min/mg of protein with deoxycytidine as a substrate (Chan et al., 1983). In another study, high activity is present in thymus, bone marrow, spleen, and skeletal muscle (Harkrader et al., 1980).

• j Expressed as nmol/min/mg of protein with S-(2-chloro-1,1,2-trifluoroethyl)-l-cysteine as a substrate (Rooseboom et al., 2002). Similar tissue distribution was observed with various SeCys conjugates and S-(1,2-dichlorovinyl)-l-cysteine (Jones et al., 1988; Rooseboom et al., 2002). Intestine activity represents the sum of large and small intestine.