In vivo depigmentation by hydroxybenzene derivatives.
Certain mono- and dihydroxybenzene derivatives are selectively cytotoxic for melanocytes in vivo, and can cause depigmentation of skin and hair. We produced selective melanocytotoxicity/hair depigmentation in C57Bl mice by injection of 0.032-1.0% p-t-butylcatechol (tBC) or p-hydroxyanisole (MMEH) in physiological saline. No depigmentation occurred on injection of 3,4-dihydroxyphenylalanine (DOPA) or 3,4-dihydroxyphenylacetic acid (DOPAC). Light- and electron-microscopic examination of biopsy specimens taken from depigmented areas indicates selective melanocyte damage as early as 2 h post-injection. Melanocytes from anagen hair are most susceptible to depigmentation. All four compounds are substrates for tyrosinase, but only tBC and MMEH generate their respective isolable 1,2-benzoquinones, tBCQ and MMEHQ. These caused depigmentation in C57Bl mice to a comparable degree to the parent compounds. DOPA- and DOPAC-quinones (DOPAQ and DOPACQ) are not spectroscopically detectable in solution, suggesting extremely low steady-state levels of these compounds. The net observed rate of reaction of the respective 1,2-quinone with 300 microM bovine serum albumin (BSA) in vitro varies widely, with tBCQ >> MMEHQ = DOPACQ >> DOPAQ. The results are consistent with a mechanism involving attack of -SH on melanosomal proteins and/or enzymes by tyrosinase-generated 1,2-quinones. This mechanism evidently differs from that involved in in vitro hydroxybenzene melanocytotoxicity of melanoma cells, in which active oxygen intermediates generated by hydroxybenzene autoxidation play a significant role. The most reliable prognosticator of in vivo depigmentation appears to be the ability of the depigmenter to form a spectroscopically stable 1,2-quinone which is capable of reacting with protein -SH.
Menter
J M
JM
Department of Medicine, Morehouse School of Medicine, Atlanta, GA 30310.
Etemadi
A A
AA
Chapman
W
W
Hollins
T D
TD
Willis
I
I
D015102:3,4-Dihydroxyphenylacetic Acid / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism / Q000633:toxicity; D001711:Biotransformation; D002083:Butylated Hydroxyanisole / Q000493:pharmacokinetics / Q000633:toxicity*; D002396:Catechols / Q000493:pharmacokinetics / Q000633:toxicity*; D004295:Dihydroxyphenylalanine / Q000493:pharmacokinetics / Q000633:toxicity*; D006197:Hair / Q000187:drug effects* / Q000473:pathology; D008544:Melanocytes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D014442:Monophenol Monooxygenase / Q000378:metabolism; D010859:Pigmentation Disorders / Q000139:chemically induced* / Q000473:pathology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013438:Sulfhydryl Compounds / Q000378:metabolism
D016227:Benzoquinones; D002396:Catechols; D013438:Sulfhydryl Compounds; D015102:3,4-Dihydroxyphenylacetic Acid; D002083:Butylated Hydroxyanisole; C038096:tert-butylcatechol; D004295:Dihydroxyphenylalanine; C051361:2-tert-butyl-4-hydroxyanisole; D014442:Monophenol Monooxygenase