Studies on the toxicity of analogues of dapsone in-vitro using rat, human and heterologously expressed metabolizing systems.
Three metabolizing systems (rat, heterologously expressed CYP3A4 and human liver) were used to evaluate 12 analogues of dapsone (4,4'diaminodiphenylsulphone) in-vitro. Methaemoglobin formation in a two-compartment and cytotoxicity in a single-compartment model were studied using human erythrocytes and neutrophils, respectively, as target cells. In the two-compartment system using rat microsomes as a generating system and methaemoglobin as an endpoint, the least potent methaemoglobin formers tested were the 2-methyl-4-propylamino (AXDD14), 2-hydroxy-4-4'amino (ABDD5) derivatives and a sulphone/trimethoprim derivative (K-130). Dapsone itself, a 2-methoxy-4-ethylamino (W10) and a 2-hydroxyl-4-ethylamino compound (ABDD39) were the most toxic. In the single-compartment cytotoxicity test using rat microsomes, AXDD14 was again among the least toxic, as was a 2-methyl 4-cyclopentyl derivative (AXDD17) and surprisingly ABDD39. The most cytotoxic compounds again included dapsone itself as well as two 2-trifluoromethyl derivatives. The only significant methaemoglobin formation and cytotoxicity shown with the heterologously expressed human CYP 3A4 was with AXDD14, which was extensively activated. Interestingly, metabolism of dapsone was low using the expressed CYP 3A4. In the two-compartment system using human liver microsomes, AXDD14, K-130 and ABDD5 were oxidized to a significantly lesser extent compared with dapsone and these preliminary findings indicate that future development of these compounds may be worthwhile.
Department of Pharmaceutical Sciences, Aston University, Birmingham, UK.
M D
MD
Coleman
S N
SN
Smith
D E
DE
Kelly
S L
SL
Kelly
J K
JK
Seydel
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003622:Dapsone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity*; D004912:Erythrocytes / Q000187:drug effects; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000633:toxicity*; D006801:Humans; D008297:Male; D008706:Methemoglobin / Q000096:biosynthesis; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley
D005493:Folic Acid Antagonists; D003622:Dapsone; D008706:Methemoglobin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human